75 results on '"Konopleva, M."'
Search Results
2. MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylation
- Author
-
Godfrey, L, Kerry, J, Thorne, R, Repapi, E, Davies, JOJ, Tapia, M, Ballabio, E, Hughes, JR, Geng, H, Konopleva, M, and Milne, T
- Subjects
Cancer Research ,hemic and lymphatic diseases ,Genetics ,Cell Biology ,Hematology ,neoplasms ,Molecular Biology - Abstract
Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we demonstrated that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. Here, we perform a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production in MLL-AF4 knockdowns, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the active transcription of both BCL-2 and MCL-1, and also represses BIM via binding of the polycomb group repressor 1 (PRC1) complex component CBX8. We further analyze MLL-AF4 activation of the BCL-2 gene using Capture C and identify a BCL-2 specific enhancer, consisting of two clusters of H3K27Ac at the 3’end of the gene. Loss of MLL-AF4 activity results in a reduction of H3K79me3 levels in the gene body and H3K27Ac levels at the 3’ BCL-2 enhancer, revealing a novel regulatory link between these two histone marks and MLL-AF4 mediated activation of BCL-2.
- Published
- 2017
3. Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL.
- Author
-
Zhao Y, Short NJ, Kantarjian HM, Chang TC, Ghate PS, Qu C, Macaron W, Jain N, Thakral B, Phillips AH, Khoury J, Garcia-Manero G, Zhang W, Fan Y, Yang H, Garris RS, Nasr LF, Kriwacki RW, Roberts KG, Konopleva M, Jabbour EJ, and Mullighan CG
- Subjects
- Humans, Female, Mutation, Male, Antineoplastic Agents, Immunological therapeutic use, Antineoplastic Agents, Immunological pharmacology, Adult, Middle Aged, Retrospective Studies, Adolescent, Inotuzumab Ozogamicin, Sialic Acid Binding Ig-like Lectin 2 genetics, Drug Resistance, Neoplasm genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Abstract: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
- View/download PDF
4. SOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies.
- Author
-
Forsberg M and Konopleva M
- Subjects
- Humans, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-bcl-2 genetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Hematologic Neoplasms drug therapy, Leukemia, Myeloid, Acute drug therapy, Sulfonamides
- Abstract
The discovery of Venetoclax (VEN) has transformed the therapeutic landscape of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). However, the response is heterogeneous with 10% to 50% of newly diagnosed AML patients not responding to hypomethylating agent (HMA) and VEN. Furthermore, up to 40% of responding patients relapse shortly. This review discusses the mechanism of action of Venetoclax and the major mechanisms of inherent and acquired resistance to VEN. VEN is highly specific to BCL-2 binding, as such other antiapoptotic proteins in BCL-2 family induce resistance. These antiapoptotic proteins can also be upregulated via a number of compensatory cell signaling pathways including PI3K/AKT/mTOR, the MAPK/ERK pathway, and mutant FLT3-ITD. Mutations can occur in BCL-2 and BAX proteins, or they can be silenced by TP53 mutations and other epigenetic changes. Changes to mitochondrial structure and metabolism can induce resistance. Key metabolic regulators include OXPHOS and alternative amino acid metabolism. Finally microenvironmental factors can influence VEN responses. This paper evaluates subsets of AML by differentiation, histology, cytogenetics and molecular markers and their different responses to VEN; with spliceosome mutations, ASXL1, NPM1 and IDH1/2 being favorable while others such as FLT3, TP53 and BCL-2 mutations being less responsive. Currently intensive multiagent chemotherapy and Venetoclax combinations such as 7+3+VEN are favored in fit younger AML patients. However, with resistant patients' subsets targeted combination therapies are becoming an increasingly attractive option. We explore the incorporation of non-BCL-2 inhibitors, next-generation BCL-2 and multi-protein agents, other inhibitors most prominently FLT-3 inhibitors in addition to Venetoclax, and other novel approaches for resolving Venetoclax resistance., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Konopleva reports grants from AbbVie, Allogene, Astra Zeneca, Cellectis, Daiichi, Forty Seven, Genentech, Gilead, MEI Pharma, Precision Bio, Rafael Pharmaceutical, Sanofi, Stemline-Menarini; personal fees from AbbVie, AstraZeneca, Auxenion, Genentech, Gilead, F. Hoffman-La Roche, Janssen, MEI Pharma, Sellas, Stemline-Menarini. In addition, Dr. Konopleva has a patent US 7,795,305 B2 CDDO-compounds and combination therapies with royalties paid to Reata Pharm., a patent Combination Therapy with a mutant IDH1 Inhibitor and a BCL-2 licensed to Eli Lilly, and a patent 62/993,166 combination of a mcl-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof pending to Novartis. Dr. Forsberg reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2024
- Full Text
- View/download PDF
5. Geographic Disparity of Outcome in Patients With Cancer Over Decades: The Surveillance, Epidemiology, and End Results.
- Author
-
Sasaki K, Morita K, Kantarjian H, Garcia-Manero G, Jabbour E, Ravandi F, Konopleva M, Borthakur G, Wierda W, Daver N, Takahashi K, DiNardo C, Bravo GM, Issa GC, Pierce SA, Soltysiak KA, Tingen MS, and Cortes JE
- Subjects
- Humans, Income, Georgia, Survival Rate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Lung Neoplasms epidemiology, Lung Neoplasms therapy
- Abstract
Background: Improvements in prevention, early detection, and effective cancer therapy have decreased cancer-related mortality; however, significant health disparities exist. Therefore, we investigated the impact of these disparities on survival., Methods: In the Surveillance, Epidemiology, and End Results, we identified 784,341 patients with cancer between 1990 and 2016 in Georgia, 68,493 between 1990 and 1999; 371,353 between 2000 and 2009; and 322,932 between 2010 and 2016. We assessed the overall survival (OS) of patients with all cancers, chronic myeloid leukemia (CML), and lung cancer, given the dramatic improvement in outcomes in patients with CML since 2000 compared to the generally considerably worse outcomes in lung cancer. In addition, we assessed the distance from each county to the Georgia Cancer Center (GCC) or the National Cancer Institute-designated Cancer Center (NCI-CC)., Results: The 5-year OS of patients with any cancer was 55%, and the 5-year OS of each county ranged from 33% to 82% (interquartile range, 51%-65%) (P < .001). In patients with lung cancer and CML, the 5-year OS rates were 15% and 52%, respectively. The geographic differences between counties were relatively small and constant over time for patients with lung cancer. However, geographic differences were more prominent in patients with CML and widened after the introduction of modern therapies. Multivariate Cox regression showed that age, median county income, race, and distance to GCC or NCI-CC were predictive factors., Conclusions: Significant disparities in cancer care exist among geographic locations. Geographic differences in survival appear more prominent when highly effective therapies are available., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
6. Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia.
- Author
-
Kuusanmäki H, Dufva O, Vähä-Koskela M, Leppä AM, Huuhtanen J, Vänttinen I, Nygren P, Klievink J, Bouhlal J, Pölönen P, Zhang Q, Adnan-Awad S, Mancebo-Pérez C, Saad J, Miettinen J, Javarappa KK, Aakko S, Ruokoranta T, Eldfors S, Heinäniemi M, Theilgaard-Mönch K, Wartiovaara-Kautto U, Keränen M, Porkka K, Konopleva M, Wennerberg K, Kontro M, Heckman CA, and Mustjoki S
- Subjects
- Animals, Mice, Humans, Proto-Oncogene Proteins c-bcl-2 genetics, Myeloid Cell Leukemia Sequence 1 Protein genetics, Cell Line, Tumor, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, bcl-X Protein genetics, Cell Differentiation, Apoptosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Megakaryoblastic, Acute drug therapy, Leukemia, Megakaryoblastic, Acute genetics, Lymphoma, B-Cell
- Abstract
Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of >500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with erythroid or megakaryocytic differentiation ex vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
7. Treatment of Cancer-related-Fatigue in Acute Hematological Malignancies: Results of a Feasibility Study of using Cognitive Behavioral Therapy.
- Author
-
Yennurajalingam S, Konopleva M, Carmack CL, Dinardo CD, Gaffney M, Michener HK, Lu Z, Stanton P, Ning J, Qiao W, and Bruera E
- Subjects
- Humans, Female, Aged, Male, Feasibility Studies, Quality of Life, Prospective Studies, Fatigue etiology, Fatigue therapy, Neoplasms, Hematologic Neoplasms complications, Hematologic Neoplasms therapy, Cognitive Behavioral Therapy
- Abstract
Background: Despite cancer related fatigue (CRF) being the most common, and debilitating symptom in patients with recently diagnosed acute hematological malignancies (HM), there are limited effective treatments for CRF in HM. The aim of this study was to determine the feasibility of cognitive behavioral therapy (CBT) for CRF in HM., Methods: In this preliminary longitudinal prospective study, HM patients diagnosed a median of one month previously with moderate to severe fatigue were enrolled. Patients received CBT in seven weekly sessions for eight weeks. Change in Functional Assessment of Cancer Illness Therapy (FACIT) - Fatigue (primary), FACT-G, Pittsburg Sleep Quality Index (PSQI), Hospital Anxiety Depression Scale (HADS), M.D. Anderson Symptom Inventory - Acute Myeloid Leukemia (MDASI-AML/MDS), and Herth Hope Index (HHI) were analyzed., Results: Twenty-seven of 36 (75 %) patients were evaluable. Adherence and satisfaction rates to the CBT intervention were 78.6% (95% CI 67.2%, 89.9%), and 92% (95% CI 76.7%, 98.3%) respectively. The median age 66, 64% female, the most common HM was AML (60%), median FACIT-F was 27. The mean (SD) improvement at end eight weeks for FACIT-F was 5.5(13.6), Cohen δ 0.4, P=0.046; and for PSQI total was 2.9 (3), Cohen δ -1, P=0.006. We also found significant improvement in HADS anxiety -2.7(4.5), P=0.049, MDASI Sleep -1.8(3.0), P=0.022, MDASI mean module symptom severity -0.7(1.6), P=0.006. However, no significant improvements were found in FACT-G, HHI, and HADS-depression scores., Conclusions: The use of CBT was feasible with improvement of CRF, sleep quality, and anxiety scores in HM. Randomized controlled trials are justified., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
8. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need.
- Author
-
Pemmaraju N, Kantarjian H, Sweet K, Wang E, Senapati J, Wilson NR, Konopleva M, Frankel AE, Gupta V, Mesa R, Ulrickson M, Gorak E, Bhatia S, Budak-Alpdogan T, Mason J, Garcia-Romero MT, Lopez-Santiago N, Cesarman-Maus G, Vachhani P, Lee S, Bhatt VR, Blum W, Walter RB, Bixby D, Gojo I, Duvic M, Rampal RK, de Lima M, Foran J, Fathi AT, Hall AC, Jacoby MA, Lancet J, Mannis G, Stein AS, Mims A, Rizzieri D, Olin R, Perl A, Schiller G, Shami P, Stone RM, Strickland S, Wieduwilt MJ, Daver N, Ravandi F, Vasu S, Guzman M, Roboz GJ, Khoury J, Qazilbash M, Aung PP, Cuglievan B, Madanat Y, Kharfan-Dabaja MA, Pawlowska A, Taylor J, Tallman M, Dhakal P, and Lane AA
- Subjects
- Child, Humans, Aged, Standard of Care, Interleukin-3 Receptor alpha Subunit, Dendritic Cells pathology, Neoplasm Recurrence, Local pathology, Acute Disease, North America, Myeloproliferative Disorders pathology, Hematologic Neoplasms pathology, Skin Neoplasms pathology
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein., (© 2023 by The American Society of Hematology.)
- Published
- 2023
- Full Text
- View/download PDF
9. Evidence supporting a role for the immune checkpoint protein B7-H3 in NK cell-mediated cytotoxicity against AML.
- Author
-
Tyagi A, Ly S, El-Dana F, Yuan B, Jaggupilli A, Grimm S, Konopleva M, Bühring HJ, and Battula VL
- Subjects
- Animals, B7 Antigens, Cell Line, Tumor, Humans, Killer Cells, Natural, Mice, Immune Checkpoint Proteins, Leukemia, Myeloid, Acute therapy
- Abstract
We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop region of B7-H3, which is known to regulate the immunosuppressive function of B7-H3. Furthermore, treatment with ChT-1A5 in combination with human NK cells significantly prolonged survival in AML patient-derived xenograft (PDX) models. Our results suggest that the ChT-1A5 antibody can inhibit the immunosuppressive function of B7-H3 protein as well as induce ADCC in B7-H3+ AML., (© 2022 by The American Society of Hematology.)
- Published
- 2022
- Full Text
- View/download PDF
10. SOHO State of the Art Updates and Next Questions:Harnessing Apoptosis in AML.
- Author
-
Saxena K, DiNardo C, Daver N, and Konopleva M
- Subjects
- Apoptosis, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cytarabine therapeutic use, Humans, Protein Kinase Inhibitors therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute genetics
- Abstract
The treatment landscape for acute myeloid leukemia has expanded significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent or low-dose cytarabine was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in acute myeloid leukemia continues to be explored., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
11. Novel Therapeutic Approaches in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Era of Targeted Therapy.
- Author
-
Wilson NR, Konopleva M, Khoury JD, and Pemmaraju N
- Subjects
- Antineoplastic Agents pharmacology, Female, Humans, Male, Antineoplastic Agents therapeutic use, Dendritic Cells pathology, Hematologic Neoplasms drug therapy
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy arising from the aberrant transformation of plasmacytoid dendritic cells (pDCs) and involving skin, bone marrow, lymph nodes, and central nervous system. Characteristically unique from other myeloid neoplasms, BPDCN cells express CD4, CD56, and CD123 as well as TCL-1 and TCF4 in almost all cases. Historically, this malignancy has exhibited a poor prognosis, with median survival of less than 2 years. Traditional treatment approaches have involved conventional cytotoxic chemotherapy followed by hematopoietic stem cell transplantation; however, patients frequently relapse with chemotherapy-resistant disease. We have recently entered a modern era of therapy with targeting of CD123, with first-in-class agent tagraxofusp, a CD123- targeted agent approved by the US Food and Drug Administration for therapy of patients with BPDCN ages 2 and older. Relapsed and refractory BPDCN remains an elusive therapeutic challenge, but better understanding of the underlying pathophysiology has led to the development of other CD123-targeted agents and combination therapy, as well as agents targeting beyond CD123. Specifically, the use of venetoclax in targeting BCL2 has been promising in BPDCN treatment. This review will focus on the underlying diagnostic markers of BPDCN which have led to novel targeted treatment strategies, as well as future directions in therapy we can expect in coming years., Competing Interests: Disclosure NP: Consulting/honorarium:AbbVie; Celgene; Stemline; Incyte; Novartis; MustangBio; Roche Diagnostics, LFB, Sanofi, ImmunoGen; Research funding/clinical trials support: Stemline; Novartis; AbbVie; Samus; Cellectis; Plexxikon; Daiichi-Sankyo; Affymetrix; Grants/funding: Affymetrix, SagerStrong Foundation. The remaining authors have stated that they have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
12. Central nervous system involvement in blastic plasmacytoid dendritic cell neoplasm.
- Author
-
Pemmaraju N, Wilson NR, Khoury JD, Jain N, Daver N, Pierce S, Jabbour E, Kadia T, DiNardo C, Garcia-Manero G, Qazilbash M, Konopleva M, and Kantarjian H
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Hematologic Neoplasms cerebrospinal fluid, Humans, Male, Middle Aged, Retrospective Studies, Young Adult, Central Nervous System pathology, Dendritic Cells pathology, Hematologic Neoplasms pathology
- Published
- 2021
- Full Text
- View/download PDF
13. Break the lifeline of AML cells.
- Author
-
Tabe Y and Konopleva M
- Subjects
- Humans, Leukemia, Myeloid, Acute
- Published
- 2021
- Full Text
- View/download PDF
14. CD123 Expression in Philadelphia Chromosome-like B Acute Lymphoblastic Leukemia/Lymphoma.
- Author
-
Lyapichev KA, Sukswai N, Angelova E, Kersh MJ, Pierce S, Konopleva M, Jain N, Jabbour EJ, Jorgensen JL, Wang SA, Medeiros LJ, Khoury JD, and Konoplev S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Philadelphia Chromosome, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma immunology, Retrospective Studies, Young Adult, Gene Expression Regulation, Leukemic, Interleukin-3 Receptor alpha Subunit genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Published
- 2021
- Full Text
- View/download PDF
15. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells.
- Author
-
Daher M, Basar R, Gokdemir E, Baran N, Uprety N, Nunez Cortes AK, Mendt M, Kerbauy LN, Banerjee PP, Shanley M, Imahashi N, Li L, Lim FLWI, Fathi M, Rezvan A, Mohanty V, Shen Y, Shaim H, Lu J, Ozcan G, Ensley E, Kaplan M, Nandivada V, Bdiwi M, Acharya S, Xi Y, Wan X, Mak D, Liu E, Jiang XR, Ang S, Muniz-Feliciano L, Li Y, Wang J, Kordasti S, Petrov N, Varadarajan N, Marin D, Brunetti L, Skinner RJ, Lyu S, Silva L, Turk R, Schubert MS, Rettig GR, McNeill MS, Kurgan G, Behlke MA, Li H, Fowlkes NW, Chen K, Konopleva M, Champlin RE, Shpall EJ, and Rezvani K
- Subjects
- Aerobiosis, Animals, Antigens, CD19 immunology, Burkitt Lymphoma pathology, Burkitt Lymphoma therapy, CRISPR-Cas Systems, Cell Line, Tumor, Gene Knockout Techniques, Glycolysis, Humans, Immune Checkpoint Inhibitors pharmacology, Interleukin-15 metabolism, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Killer Cells, Natural transplantation, Mechanistic Target of Rapamycin Complex 1 physiology, Mice, Neoplasm Proteins genetics, Neoplasm Proteins physiology, Proto-Oncogene Proteins c-akt physiology, Receptors, Chimeric Antigen, Signal Transduction physiology, Suppressor of Cytokine Signaling Proteins genetics, Suppressor of Cytokine Signaling Proteins physiology, Xenograft Model Antitumor Assays, Fetal Blood cytology, Immunotherapy, Adoptive, Interleukin-15 genetics, Killer Cells, Natural drug effects, Neoplasm Proteins antagonists & inhibitors, Suppressor of Cytokine Signaling Proteins antagonists & inhibitors
- Abstract
Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible Src homology 2-containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation "armored" chimeric antigen receptor (CAR) engineering of cord blood-derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell antitumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15-secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
- View/download PDF
16. Mechanisms of Response and Resistance to AML Therapies.
- Author
-
Stoilova B, Moore R, Metzner M, Zheng Z, Konopleva M, DiNardo C, and Vyas P
- Subjects
- Drug Resistance, Neoplasm, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Molecular Targeted Therapy, Single-Cell Analysis, Leukemia, Myeloid, Acute drug therapy
- Published
- 2020
- Full Text
- View/download PDF
17. Harnessing Apoptosis in AML.
- Author
-
Saxena K, DiNardo C, Daver N, and Konopleva M
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Apoptosis immunology, Clinical Trials, Phase III as Topic, Humans, Leukemia, Myeloid, Acute immunology, Randomized Controlled Trials as Topic, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology
- Abstract
The treatment landscape for AML has grown significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC) was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in AML continues to be explored., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
18. Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia.
- Author
-
Richard-Carpentier G, Jabbour E, Short NJ, Rausch CR, Savoy JM, Bose P, Yilmaz M, Jain N, Borthakur G, Ohanian M, Alvarado Y, Rytting M, Kebriaei P, Konopleva M, Kantarjian H, and Ravandi F
- Subjects
- Adult, Aged, Cyclophosphamide administration & dosage, Dexamethasone administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Female, Humans, Male, Middle Aged, Survival Rate, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Sulfonamides administration & dosage
- Abstract
Background: Patients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown., Patient and Methods: We retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution., Results: Thirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts < 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for > 14 days per cycle., Conclusion: Combination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
19. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML.
- Author
-
DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, Thijssen R, Pomilio G, Ivey A, Salmon JM, Glytsou C, Fleming SA, Zhang Q, Ma H, Patel KP, Kornblau SM, Xu Z, Chua CC, Chen X, Blombery P, Flensburg C, Cummings N, Aifantis I, Kantarjian H, Huang DCS, Roberts AW, Majewski IJ, Konopleva M, and Wei AH
- Subjects
- Age Factors, Aged, Aged, 80 and over, Alleles, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Computational Biology methods, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Nucleophosmin, Prognosis, Retreatment, Sulfonamides administration & dosage, Sulfonamides adverse effects, Sulfonamides therapeutic use, Treatment Failure, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
20. Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation?
- Author
-
Ciurea SO, Kongtim P, Varma A, Rondon G, Chen J, Srour S, Bashir Q, Alousi A, Mehta R, Oran B, Popat U, Hosing C, Olson A, Daver N, Konopleva M, and Champlin RE
- Subjects
- Age Factors, Aged, Antineoplastic Agents therapeutic use, Busulfan therapeutic use, Female, Humans, Male, Melphalan therapeutic use, Middle Aged, Transplantation, Homologous methods, Treatment Outcome, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Transplantation Conditioning methods
- Abstract
The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
21. Amino acid metabolism in hematologic malignancies and the era of targeted therapy.
- Author
-
Tabe Y, Lorenzi PL, and Konopleva M
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Arginine metabolism, Asparagine metabolism, Cysteine metabolism, Glutamine metabolism, Humans, Metabolic Networks and Pathways drug effects, Molecular Targeted Therapy, Tumor Microenvironment drug effects, Amino Acids metabolism, Hematologic Neoplasms drug therapy, Hematologic Neoplasms metabolism
- Abstract
Tumor cells rewire metabolic pathways to adapt to their increased nutritional demands for energy, reducing equivalents, and cellular biosynthesis. Alternations in amino acid metabolism are 1 modality for satisfying those demands. Amino acids are not only components of proteins but also intermediate metabolites fueling multiple biosynthetic pathways. Amino acid-depletion therapies target amino acid uptake and catabolism using heterologous enzymes or recombinant or engineered human enzymes. Notably, such therapies have minimal effect on normal cells due to their lower demand for amino acids compared with tumor cells and their ability to synthesize the targeted amino acids under conditions of nutrient stress. Here, we review novel aspects of amino acid metabolism in hematologic malignancies and deprivation strategies, focusing on 4 key amino acids: arginine, asparagine, glutamine, and cysteine. We also present the roles of amino acid metabolism in the immunosuppressive tumor microenvironment and in drug resistance. This summary also offers an argument for the reclassification of amino acid-depleting enzymes as targeted therapeutic agents., (© 2019 by The American Society of Hematology.)
- Published
- 2019
- Full Text
- View/download PDF
22. Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.
- Author
-
Ragon BK, Odenike O, Baer MR, Stock W, Borthakur G, Patel K, Han L, Chen H, Ma H, Joseph L, Zhao Y, Baggerly K, Konopleva M, and Jain N
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Diamines administration & dosage, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Male, Middle Aged, Pyrazoles administration & dosage, Pyridones administration & dosage, Pyrimidinones administration & dosage, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Genes, ras, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 2 antagonists & inhibitors, Mutation, Proto-Oncogene Proteins c-akt antagonists & inhibitors
- Abstract
Background: With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML)., Patients and Methods: The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795)., Results: Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML., Conclusion: Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
23. Venetoclax-based therapies for acute myeloid leukemia.
- Author
-
Guerra VA, DiNardo C, and Konopleva M
- Subjects
- Aminopyridines therapeutic use, Benzimidazoles therapeutic use, Clinical Trials as Topic, Cytarabine therapeutic use, Daunorubicin therapeutic use, Glycine analogs & derivatives, Glycine therapeutic use, Humans, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Phenylurea Compounds therapeutic use, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism, Pyridines therapeutic use, Triazines therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Leukemia, Myeloid, Acute drug therapy, Sulfonamides therapeutic use
- Abstract
The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
24. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.
- Author
-
DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, and Letai A
- Subjects
- Aged, Aged, 80 and over, Azacitidine administration & dosage, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Cohort Studies, Decitabine administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute pathology, Male, Maximum Tolerated Dose, Prognosis, Sulfonamides administration & dosage, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m
2 , days 1-5, intravenously [IV]) or azacitidine (75 mg/m2 , days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773)., (© 2019 by The American Society of Hematology.)- Published
- 2019
- Full Text
- View/download PDF
25. A Pilot Trial of Lirilumab With or Without Azacitidine for Patients With Myelodysplastic Syndrome.
- Author
-
Yalniz FF, Daver N, Rezvani K, Kornblau S, Ohanian M, Borthakur G, DiNardo CD, Konopleva M, Burger J, Gasior Y, Pierce S, Kantarjian H, and Garcia-Manero G
- Subjects
- Aged, Aged, 80 and over, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Male, Middle Aged, Myelodysplastic Syndromes pathology, Pilot Projects, Prognosis, Receptors, KIR antagonists & inhibitors, Survival Rate, Antibodies, Monoclonal therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Myelodysplastic Syndromes drug therapy
- Abstract
Background: Enhancement of natural killer cell activity by blocking interactions between killer immunoglobulin (Ig)-like receptors (KIRs) and human leukocyte antigen-C (HLA-C) molecules can improve outcomes in myeloid malignancies. Lirilumab is a human IgG4 monoclonal antibody that blocks KIR/HLA-C interaction. We designed a study to evaluate the safety and efficacy of lirilumab as a single agent and in combination with azacitidine in patients with myelodysplastic syndrome (MDS)., Patients and Methods: Adult patients with MDS who had not received previous hypomethylating agents were included. Lower-risk MDS patients received single-agent lirilumab (3 mg/kg); higher-risk patients received azacitidine (75 mg/m
2 /day for 7 days) in combination with lirilumab (3 mg/kg, on day 7), in a 28-day cycle. Responses were evaluated according to 2006 International Working Group criteria., Results: A total of 10 patients including 8 with higher and 2 with lower-risk enrolled. The median age was 70 (range, 50-84) years and 4 (40%) had complex cytogenetics. Baseline molecular mutations included TP53 (n = 5), TET2 (n = 3), and NRAS (n = 2). Patients received a median of 4 (range, 2-13) and 9 (range, 5-14) cycles of treatment with azacitidine with lirilumab and single-agent lirilumab, respectively. Two patients achieved complete remission (CR), 5 marrow CR, and 3 had stable disease. The median event-free survival for the entire cohort was 8 months (95% confidence interval, 4 months to not reached), and the median overall survival has not yet been reached. Five patients experienced 8 episodes of Grade ≥3 adverse events attributable to study drug, with the most frequent being infection or neutropenic fever (75%)., Conclusion: Lirilumab either as a single agent as well as used in combination with azacitidine has clinical activity in patients with MDS. Further studies are needed to confirm our findings., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
26. BCL-2 inhibition in AML: an unexpected bonus?
- Author
-
Konopleva M and Letai A
- Subjects
- Azacitidine therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cytarabine therapeutic use, Decitabine therapeutic use, Humans, Sulfonamides therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 metabolism
- Abstract
B-cell lymphoma 2 (BCL-2) was discovered at the breakpoint of the t(14;18) in follicular lymphoma >30 years ago. Although inhibition of BCL-2 first proved valuable in lymphoid malignancies, clinical progress in myeloid malignancies lagged. Here, we summarize the basic biology and preclinical results that spurred clinical BCL-2 inhibition in acute myeloid leukemia (AML). Response rates and toxicity for venetoclax in combination with standard AML agents, such as azacitidine, decitabine, and low-dose cytarabine, compare favorably with conventional induction chemotherapy. Durability of response requires further study., (© 2018 by The American Society of Hematology.)
- Published
- 2018
- Full Text
- View/download PDF
27. Safety and Efficacy of Blinatumomab in Combination With a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-positive Leukemia.
- Author
-
Assi R, Kantarjian H, Short NJ, Daver N, Takahashi K, Garcia-Manero G, DiNardo C, Burger J, Cortes J, Jain N, Wierda W, Chamoun S, Konopleva M, and Jabbour E
- Subjects
- Adult, Aged, Antibodies, Bispecific administration & dosage, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl genetics, Humans, Kaplan-Meier Estimate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Middle Aged, Neoplasm Recurrence, Local, Protein Kinase Inhibitors administration & dosage, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
- Abstract
Objective: The treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia has been revolutionized with the introduction of tyrosine kinase inhibitors (TKIs) and the combination of these agents with chemotherapy. Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody with clinical activity as single-agent in the relapsed setting and independent of BCR-ABL1 mutational status, including T315I. The combination of blinatumomab with a TKI may further improve outcomes for this high-risk population, including higher eradication of minimal residual disease and minimize the use of chemotherapy., Patients and Methods: We retrospectively studied 12 adults with relapsed/refractory Ph+ acute lymphoblastic leukemia (n = 9) and chronic myeloid leukemia in blast crisis (n = 3), treated with the combination blinatumomab and a TKI (ponatinib, n = 8; dasatinib, n = 3; bosutinib, n = 1). All patients have previously failed at least 1 line of chemotherapy, including allogeneic stem cell transplantation, and 1 class of TKIs. Patients were treated for either overt hematologic relapse (n = 6) or persistent minimal residual disease following other regimens (n = 6)., Results: The complete hematologic, cytogenetic, and molecular response rates were 50% (3/6), 71% (5/7), and 75% (9/12), respectively. Two cases of grade 2 cytokine release syndrome were observed, all of which resolved with steroids and tocilizumab. No cardiovascular adverse events were encountered. With a median follow-up of 8 months, the median survival was not reached; the 6-month and 1-year overall survival rates were 73%., Conclusions: The combination of blinatumomab with TKI is safe and effective in patients with relapsed/refractory Ph+ disease. Prospective studies are warranted., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
28. More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia.
- Author
-
Montalban-Bravo G, Benton CB, Wang SA, Ravandi F, Kadia T, Cortes J, Daver N, Takahashi K, DiNardo C, Jabbour E, Borthakur G, Konopleva M, Pierce S, Bueso-Ramos C, Patel K, Kornblau S, Kantarjian H, Young KH, Garcia-Manero G, and Andreeff M
- Subjects
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Retrospective Studies, Survival Rate, Leukemia, Erythroblastic, Acute drug therapy, Leukemia, Erythroblastic, Acute genetics, Leukemia, Erythroblastic, Acute mortality, Mutation, Tumor Suppressor Protein p53 genetics
- Published
- 2017
- Full Text
- View/download PDF
29. Long-term outcome of acute promyelocytic leukemia treated with all- trans -retinoic acid, arsenic trioxide, and gemtuzumab.
- Author
-
Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, and Ravandi F
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Aminoglycosides administration & dosage, Aminoglycosides adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Arsenic Trioxide, Arsenicals administration & dosage, Arsenicals adverse effects, Disease-Free Survival, Female, Follow-Up Studies, Gemtuzumab, Humans, Kaplan-Meier Estimate, Leukemia, Promyelocytic, Acute mortality, Male, Middle Aged, Oxides administration & dosage, Oxides adverse effects, Polymerase Chain Reaction, Treatment Outcome, Tretinoin administration & dosage, Tretinoin adverse effects, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy
- Abstract
The combination of all- trans -retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m
2 daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m2 on day 1) added to high-risk patients (white blood cell count, >10 × 109 /L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen., (© 2017 by The American Society of Hematology.)- Published
- 2017
- Full Text
- View/download PDF
30. Ph-like acute lymphoblastic leukemia: a high-risk subtype in adults.
- Author
-
Jain N, Roberts KG, Jabbour E, Patel K, Eterovic AK, Chen K, Zweidler-McKay P, Lu X, Fawcett G, Wang SA, Konoplev S, Harvey RC, Chen IM, Payne-Turner D, Valentine M, Thomas D, Garcia-Manero G, Ravandi F, Cortes J, Kornblau S, O'Brien S, Pierce S, Jorgensen J, Shaw KR, Willman CL, Mullighan CG, Kantarjian H, and Konopleva M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Cohort Studies, Disease-Free Survival, Female, Gene Expression Regulation, Leukemic, Hispanic or Latino genetics, Humans, Janus Kinase 2 genetics, Male, Middle Aged, Mutation, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Proportional Hazards Models, Receptors, Cytokine genetics, Risk Factors, Transcriptome, Treatment Outcome, Young Adult, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are conflicting data on the incidence and prognosis of Ph-like ALL in adults. Patients with newly diagnosed B-cell ALL (B-ALL) who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells. Of 148 patients, 33.1% had Ph-like, 31.1% had Ph
+ , and 35.8% had other B-ALL subtypes (B-other). Within the Ph-like ALL cohort, 61% had cytokine receptor-like factor 2 (CRLF2) overexpression. Patients with Ph-like ALL had significantly worse overall survival (OS), and event-free survival compared with B-other with a 5-year survival of 23% (vs 59% for B-other, P = .006). Sixty-eight percent of patients with Ph-like ALL were of Hispanic ethnicity. The following were associated with inferior OS on multivariable analysis: age (hazard ratio [HR], 3.299; P < .001), white blood cell count (HR, 1.910; P = .017), platelet count (HR, 7.437; P = .005), and Ph-like ALL (HR, 1.818; P = .03). Next-generation sequencing of the CRLF2+ group identified mutations in the JAK-STAT and Ras pathway in 85% of patients, and 20% had a CRLF2 mutation. Within the CRLF2+ group, JAK2 mutation was associated with inferior outcomes. Our findings show high frequency of Ph-like ALL in adults, an increased frequency of Ph-like ALL in adults of Hispanic ethnicity, significantly inferior outcomes of adult patients with Ph-like ALL, and significantly worse outcomes in the CRLF2+ subset of Ph-like ALL. Novel strategies are needed to improve the outcome of these patients., (© 2017 by The American Society of Hematology.)- Published
- 2017
- Full Text
- View/download PDF
31. Cotargeting BCL-2 and BCL-XL for maximal efficacy in ALL.
- Author
-
Daver N and Konopleva M
- Subjects
- Apoptosis, Humans, Proto-Oncogene Proteins c-bcl-2, bcl-X Protein
- Published
- 2016
- Full Text
- View/download PDF
32. High Expression of Human Homologue of Murine Double Minute 4 and the Short Splicing Variant, HDM4-S, in Bone Marrow in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome.
- Author
-
Han X, Medeiros LJ, Zhang YH, You MJ, Andreeff M, Konopleva M, and Bueso-Ramos CE
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Bone Marrow pathology, Bone Marrow Cells metabolism, Cell Cycle Proteins, Cell Line, Tumor, Child, Child, Preschool, Chromosome Aberrations, Female, Gene Expression Regulation, Leukemic, Genes, ras, Humans, Immunohistochemistry, Infant, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, Nuclear Proteins metabolism, Proto-Oncogene Proteins metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Small Interfering genetics, Young Adult, fms-Like Tyrosine Kinase 3 genetics, Alternative Splicing, Gene Expression, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Nuclear Proteins genetics, Proto-Oncogene Proteins genetics
- Abstract
The human homologue of murine double minute 2 (HDM2) and HDM4 negatively regulate p53. HDM4 has not been assessed in acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We examined the expression of HDM4 and the short splicing variant, HDM4-S, in bone marrow samples obtained from 85 and 23 patients with AML and MDS, respectively, and 18 negative tumor staging bone marrow samples (used as the control). Immunohistochemical staining showed that HDM4 was overexpressed in 78 AML cases (92%) and 12 MDS cases (52%) compared with 1 stressed bone marrow sample (6%). Quantitative reverse transcriptase-polymerase chain reaction analysis of 8 AML and 11 low-grade (LG)-MDS cases confirmed that HDM4 and HDM4-S mRNA expression were also elevated in all AML cases. HDM4 and HDM4-S mRNA expression was elevated in 3 (27%) and 10 (91%) LG-MDS cases, respectively. HDM4 and HDM4-S mRNA levels were higher in those with AML than in those with LG-MDS. In leukemia cell lines, HEL and U937 predominantly expressed HDM4-S. In contrast, NALM6 expressed HDM4 and HDM4-S. Downregulation of HDM4 expression by treatment with small interfering RNA in NALM6 and HEL cells induced p21 expression but not increased apoptotic activity. Our results indicate that HDM4 is a potential therapeutic target in patients with AML or MDS., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
33. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype.
- Author
-
Jain N, Lamb AV, O'Brien S, Ravandi F, Konopleva M, Jabbour E, Zuo Z, Jorgensen J, Lin P, Pierce S, Thomas D, Rytting M, Borthakur G, Kadia T, Cortes J, Kantarjian HM, and Khoury JD
- Subjects
- Adolescent, Adult, Aged, Antigens, CD1 genetics, CD3 Complex genetics, Cell Differentiation, Disease-Free Survival, Female, Follow-Up Studies, Humans, Immunophenotyping, Male, Middle Aged, Precursor Cells, T-Lymphoid immunology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Prognosis, Proportional Hazards Models, Recurrence, Remission Induction, Risk Factors, Treatment Outcome, Young Adult, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a recently recognized high-risk T lymphoblastic leukemia/lymphoma (T-ALL/LBL) subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL/LBL are poorly characterized. In this study, we compared the outcomes of adults with ETP-ALL/LBL who received treatment on frontline regimens with those of patients with other T-ALL/LBL immunophenotypic subtypes. Patients with newly diagnosed T-ALL/LBL who received frontline chemotherapy between the years 2000 and 2014 at The University of Texas MD Anderson Cancer Center were identified and immunophenotypically categorized into early, thymic, and mature per the World Health Organization (WHO) classification using CD1a and surface CD3 status. Patients with ETP-ALL/LBL were identified on the basis of the following immunophenotypes: CD1a(-), CD8(-), CD5(-)(dim), and positivity for 1 or more stem cell or myeloid antigens. A total of 111 patients with T-ALL/LBL (68% T-ALL; 32% T-LBL) with adequate immunophenotype data were identified. The median age was 30 years (range, 13-79). There was no difference in the outcomes of patients based on the WHO subtypes. Nineteen patients (17%) had ETP-ALL/LBL. The complete remission rate /complete remission with incomplete platelet recovery rate in patients with ETP-ALL/LBL was significantly lower than that of non-ETP-ALL/LBL patients (73% vs 91%;P= .03). The median overall survival for patients with ETP-ALL/LBL was 20 months vs not reached for the non-ETP-ALL/LBL patients (P= .008). ETP-ALL/LBL represents a high-risk disease subtype of adult ALL. Novel treatment strategies are needed to improve treatment outcomes in this T-ALL/LBL subset., (© 2016 by The American Society of Hematology.)
- Published
- 2016
- Full Text
- View/download PDF
34. Clofarabine Plus Low-Dose Cytarabine Is as Effective as and Less Toxic Than Intensive Chemotherapy in Elderly AML Patients.
- Author
-
Takahashi K, Kantarjian H, Garcia-Manero G, Borthakur G, Kadia T, DiNardo C, Jabbour E, Pierce S, Estrov Z, Konopleva M, Andreeff M, Ravandi F, and Cortes J
- Subjects
- Adenine Nucleotides administration & dosage, Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Arabinonucleosides administration & dosage, Clofarabine, Cohort Studies, Combined Modality Therapy, Cytarabine administration & dosage, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Retreatment, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Introduction: Most patients with acute myeloid leukemia (AML) age ≥ 60 years are not offered intensive induction because of high mortality. Phase 2 studies of clofarabine plus low-dose cytarabine (CLDA) as frontline therapy for elderly AML patients demonstrated high response and acceptable toxicity., Patients and Methods: We hypothesized that induction therapy with CLDA provides equivalent outcomes to but is less toxic than intensive induction in these patients. To test this hypothesis, we conducted a propensity score-matched comparison of AML patients age ≥ 60 years given induction CLDA versus idarubicin and cytarabine (IA). Ninety-five patients in both groups were matched according to their propensity score., Results: We did not observe statistically significant differences in response, overall survival, or mortality rate between the two induction regimens. However, CLDA produced significantly fewer grade 3 or worse toxicities (46% for CLDA vs. 62% for IA; P = .03). Furthermore, among responders, the median response duration was significantly longer with CLDA when we censored patients who underwent stem cell transplantation (15.9 months for CLDA vs. 7.0 months for IA; P = .033)., Conclusion: Compared with intensive induction, CLDA offers equivalent responses and survival but less toxicity in clinically well-matched cohorts of elderly AML patients. Prospective randomized trials to confirm these findings are warranted., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
35. Targeting leukemia's "fatty tooth".
- Author
-
Samudio I and Konopleva M
- Subjects
- Humans, Carnitine analogs & derivatives, Carnitine O-Palmitoyltransferase antagonists & inhibitors, Drug Delivery Systems, Fatty Acids metabolism, Leukemia, Myeloid, Acute drug therapy, Neoplasm Proteins antagonists & inhibitors
- Abstract
In this issue of Blood, Ricciardi et al report a novel fatty acid oxidation (FAO) inhibitor, ST1326, that effectively inhibits proliferation, survival, and chemoresistance in leukemia cell lines and primary samples.
- Published
- 2015
- Full Text
- View/download PDF
36. Pharmacokinetics of posaconazole prophylaxis of patients with acute myeloid leukemia.
- Author
-
Mattiuzzi G, Yilmaz M, Kantarjian H, Borthakur G, Konopleva M, Jabbour E, Brown Y, Pierce S, and Cortes J
- Subjects
- Adult, Aged, Antifungal Agents adverse effects, Antifungal Agents blood, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Humans, Induction Chemotherapy, Leukemia, Myeloid, Acute drug therapy, Male, Middle Aged, Prospective Studies, Salvage Therapy, Triazoles adverse effects, Triazoles blood, Antifungal Agents pharmacokinetics, Leukemia, Myeloid, Acute blood, Mycoses prevention & control, Triazoles pharmacokinetics
- Abstract
Antifungal prophylaxis is routinely given to patients with hematologic malignancies at high risk for invasive fungal infections (IFI), yet breakthrough IFI may still occur. Posaconazole emerged as an excellent alternative for fungal prophylaxis in high-risk patients. There is limited data about pharmacokinetics and plasma concentrations of posaconazole when given as prophylaxis in patients with hematologic malignancies. We recruited 20 adult patients for prospective, open label trial of posaconazole given as a prophylaxis in patients with newly diagnosed acute myeloid leukemia (AML) undergoing induction chemotherapy or first salvage therapy. The median age of all patients was 65 years and received prophylaxis for a median of 38 days (range: 5-42 days).Ten patients (50%) completed 42 days on posaconazole prophylaxis. Median plasma posaconazole levels showed no statistical difference across gender, body surface area, patients developing IFI, and patients acquiring grade 3 or 4 elevation of liver enzymes. However, there was an overall trend for higher trough concentrations among patients with no IFI than those with IFI. Pharmacokinetics of posaconazole varies from patient to patient, and AML patients receiving induction chemotherapy who never develop IFI tend to have higher plasma concentrations after oral administration of posaconazole., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
37. Phosphorylation of GSK3α/β correlates with activation of AKT and is prognostic for poor overall survival in acute myeloid leukemia patients.
- Author
-
Ruvolo PP, Qiu Y, Coombes KR, Zhang N, Neeley ES, Ruvolo VR, Hail N Jr, Borthakur G, Konopleva M, Andreeff M, and Kornblau SM
- Abstract
Background: Acute myeloid leukemia (AML) patients with highly active AKT tend to do poorly. Cell cycle arrest and apoptosis are tightly regulated by AKT via phosphorylation of GSK3α and β isoforms which inactivates these kinases. In the current study we examine the prognostic role of AKT mediated GSK3 phosphorylation in AML., Methods: We analyzed GSK3α/β phosphorylation by reverse phase protein analysis (RPPA) in a cohort of 511 acute myeloid leukemia (AML) patients. Levels of phosphorylated GSK3 were correlated with patient characteristics including survival and with expression of other proteins important in AML cell survival., Results: High levels of p-GSK3α/β correlated with adverse overall survival and a lower incidence of complete remission duration in patients with intermediate cytogenetics, but not in those with unfavorable cytogenetics. Intermediate cytogenetic patients with FLT3 mutation also fared better respectively when p-GSK3α/β levels were lower. Phosphorylated GSK3α/β expression was compared and contrasted with that of 229 related cell cycle arrest and/or apoptosis proteins. Consistent with p-GSK3α/β as an indicator of AKT activation, RPPA revealed that p-GSK3α/β positively correlated with phosphorylation of AKT, BAD, and P70S6K, and negatively correlated with β-catenin and FOXO3A. PKCδ also positively correlated with p-GSK3α/β expression, suggesting crosstalk between the AKT and PKC signaling pathways in AML cells., Conclusions: These findings suggest that AKT-mediated phosphorylation of GSK3α/β may be beneficial to AML cell survival, and hence detrimental to the overall survival of AML patients. Intrinsically, p-GSK3α/β may serve as an important adverse prognostic factor for a subset of AML patients.
- Published
- 2015
- Full Text
- View/download PDF
38. Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor (-)BI97D6 overcomes ABT-737 resistance in acute myeloid leukemia.
- Author
-
Pan R, Ruvolo VR, Wei J, Konopleva M, Reed JC, Pellecchia M, Andreeff M, and Ruvolo PP
- Subjects
- Animals, Blotting, Western, Cell Proliferation drug effects, Female, Flow Cytometry, Gossypol pharmacology, Humans, Immunoenzyme Techniques, Immunoprecipitation, Leukemia, Myeloid, Acute metabolism, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Piperazines pharmacology, Proto-Oncogene Proteins c-bcl-2 metabolism, Stem Cells cytology, Stem Cells drug effects, Stem Cells metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Apoptosis drug effects, Biphenyl Compounds pharmacology, Drug Resistance, Neoplasm drug effects, Gossypol analogs & derivatives, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Naphthoquinones pharmacology, Nitrophenols pharmacology, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides pharmacology
- Abstract
Overexpression of antiapoptotic Bcl-2 proteins such as Bcl-2, Bcl-xL, and Mcl-1 is widely associated with tumor initiation, progression, and chemoresistance. Furthermore, it has been demonstrated that Mcl-1 upregulation renders several types of cancers resistant to the Bcl-2/Bcl-xL inhibitors ABT-737 and ABT-263. The emerging importance of Mcl-1 in pathogenesis and drug resistance makes it a high-priority therapeutic target. In this study, we showed that inhibition of Mcl-1 with a novel pan-Bcl-2 inhibitor (-)BI97D6 potently induced apoptosis in acute myeloid leukemia (AML) cells. (-)BI97D6 induced hallmarks of mitochondrial apoptosis, disrupted Mcl-1/Bim and Bcl-2/Bax interactions, and stimulated cell death via the Bak/Bax-dependent mitochondrial apoptosis pathway, suggesting on-target mechanisms. As a single agent, this pan-Bcl-2 inhibitor effectively overcame AML cell apoptosis resistance mediated by Mcl-1 or by interactions with bone marrow mesenchymal stromal cells. (-)BI97D6 was also potent in killing refractory primary AML cells. Importantly, (-)BI97D6 killed AML leukemia stem/progenitor cells while largely sparing normal hematopoietic stem/progenitor cells. These findings demonstrate that pan-Bcl-2 inhibition by an Mcl-1-targeting inhibitor not only overcomes intrinsic drug resistance ensuing from functional redundancy of Bcl-2 proteins, but also abrogates extrinsic resistance caused by the protective tumor microenvironment., (© 2015 by The American Society of Hematology.)
- Published
- 2015
- Full Text
- View/download PDF
39. Antileukemia activity of the novel peptidic CXCR4 antagonist LY2510924 as monotherapy and in combination with chemotherapy.
- Author
-
Cho BS, Zeng Z, Mu H, Wang Z, Konoplev S, McQueen T, Protopopova M, Cortes J, Marszalek JR, Peng SB, Ma W, Davis RE, Thornton DE, Andreeff M, and Konopleva M
- Subjects
- Animals, Drug Resistance, Neoplasm drug effects, Humans, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred NOD, Mice, SCID, Mice, Transgenic, Receptors, CXCR4 antagonists & inhibitors, Tumor Cells, Cultured, U937 Cells, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Peptides, Cyclic administration & dosage
- Abstract
Targeting the stromal cell-derived factor 1α (SDF-1α)/C-X-C chemokine receptor type 4 (CXCR4) axis has been shown to be a promising therapeutic approach to overcome chemoresistance in acute myeloid leukemia (AML). We investigated the antileukemia efficacy of a novel peptidic CXCR4 antagonist, LY2510924, in preclinical models of AML. LY2510924 rapidly and durably blocked surface CXCR4 and inhibited stromal cell-derived factor 1 (SDF-1)α-induced chemotaxis and prosurvival signals of AML cells at nanomolar concentrations more effectively than the small-molecule CXCR4 antagonist AMD3100. In vitro, LY2510924 chiefly inhibited the proliferation of AML cells with little induction of cell death and reduced protection against chemotherapy by stromal cells. In mice with established AML, LY2510924 caused initial mobilization of leukemic cells into the circulation followed by reduction in total tumor burden. LY2510924 had antileukemia effects as monotherapy as well as in combination with chemotherapy. Gene expression profiling of AML cells isolated from LY2510924-treated mice demonstrated changes consistent with loss of SDF-1α/CXCR4 signaling and suggested reduced proliferation and induction of differentiation, which was proved by showing the attenuation of multiple prosurvival pathways such as PI3K/AKT, MAPK, and β-catenin and myeloid differentiation in vivo. Effective disruption of the SDF-1α/CXCR4 axis by LY2510924 may translate into effective antileukemia therapy in future clinical applications., (© 2015 by The American Society of Hematology.)
- Published
- 2015
- Full Text
- View/download PDF
40. Secondary mutations as mediators of resistance to targeted therapy in leukemia.
- Author
-
Daver N, Cortes J, Ravandi F, Patel KP, Burger JA, Konopleva M, and Kantarjian H
- Subjects
- Antineoplastic Agents therapeutic use, Humans, Leukemia drug therapy, Drug Resistance, Neoplasm genetics, Leukemia genetics, Mutation, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases genetics
- Abstract
The advent of small molecule-based targeted therapy has improved the treatment of both acute and chronic leukemias. Resistance to small molecule inhibitors has emerged as a common theme. The most frequent mode of acquired resistance is the acquisition of point mutations in the kinase domain. FLT3 inhibitors have improved response rates in FLT3-mutated acute myeloid leukemia (AML). The occurrence of the ATP-binding site and activation loop mutations confers varying degrees of resistance to the individual FLT3 inhibitors. Second-generation FLT3 inhibitors such as crenolanib may overcome the resistance of these mutations. Furthermore, nonmutational mechanisms of resistance such as prosurvival pathways and bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domain mutations. More recently, point mutations conferring resistance to the Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia, arsenic trioxide in acute promyelocytic leukemia, and the BH3-mimetic ABT199 in lymphoma have been identified. In chronic myeloid leukemia, the emergence of tyrosine kinase domain mutations has historically been the dominant mechanism of resistance. The early identification of secondary point mutations and their downstream effects along with the development of second- or third-generation inhibitors and rationally designed small molecule combinations are potential strategies to overcome mutation-mediated resistance., (© 2015 by The American Society of Hematology.)
- Published
- 2015
- Full Text
- View/download PDF
41. Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia.
- Author
-
Mallampati S, Leng X, Ma H, Zeng J, Li J, Wang H, Lin K, Lu Y, Yang Y, Sun B, Gong Y, Lee JS, Konopleva M, Andreeff M, Arlinghaus RB, Cai Z, Fang B, Shen H, Han X, Hirsch-Ginsberg CF, Gao X, Paranjape AN, Mani SA, Clise-Dwyer K, and Sun X
- Subjects
- Animals, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Transformation, Neoplastic drug effects, Fusion Proteins, bcr-abl genetics, Gene Expression Profiling, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells metabolism, Mice, Oligonucleotide Array Sequence Analysis, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Signal Transduction drug effects, Tumor Cells, Cultured, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl metabolism, Mesenchymal Stem Cells pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Kinase Inhibitors pharmacology
- Abstract
Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL., (© 2015 by The American Society of Hematology.)
- Published
- 2015
- Full Text
- View/download PDF
42. A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.
- Author
-
Perez-Andreu V, Roberts KG, Xu H, Smith C, Zhang H, Yang W, Harvey RC, Payne-Turner D, Devidas M, Cheng IM, Carroll WL, Heerema NA, Carroll AJ, Raetz EA, Gastier-Foster JM, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Rowe JM, Luger SM, Tallman MS, Dean M, Burchard EG, Torgerson DG, Yue F, Wang Y, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Loh ML, Willman CL, Hunger SP, Mullighan CG, and Yang JJ
- Subjects
- Adolescent, Adult, Female, GATA3 Transcription Factor genetics, Genetic Loci, Humans, Male, Neoplasm Proteins genetics, Philadelphia Chromosome, Risk Factors, Young Adult, Alleles, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 × 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.
- Published
- 2015
- Full Text
- View/download PDF
43. Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients.
- Author
-
Frankel AE, Woo JH, Ahn C, Pemmaraju N, Medeiros BC, Carraway HE, Frankfurt O, Forman SJ, Yang XA, Konopleva M, Garnache-Ottou F, Angelot-Delettre F, Brooks C, Szarek M, and Rowinsky E
- Subjects
- Adult, Aged, Dendritic Cells immunology, Diphtheria Toxin administration & dosage, Diphtheria Toxin adverse effects, Diphtheria Toxin therapeutic use, Hematologic Neoplasms immunology, Humans, Interleukin-3 administration & dosage, Interleukin-3 adverse effects, Interleukin-3 therapeutic use, Male, Molecular Targeted Therapy, Prospective Studies, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins adverse effects, Skin Neoplasms immunology, Treatment Outcome, Dendritic Cells pathology, Hematologic Neoplasms pathology, Hematologic Neoplasms therapy, Receptors, Interleukin-3 antagonists & inhibitors, Recombinant Fusion Proteins therapeutic use, Skin Neoplasms pathology, Skin Neoplasms therapy
- Abstract
This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579., (© 2014 by The American Society of Hematology.)
- Published
- 2014
- Full Text
- View/download PDF
44. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance.
- Author
-
Jacamo R, Chen Y, Wang Z, Ma W, Zhang M, Spaeth EL, Wang Y, Battula VL, Mak PY, Schallmoser K, Ruvolo P, Schober WD, Shpall EJ, Nguyen MH, Strunk D, Bueso-Ramos CE, Konoplev S, Davis RE, Konopleva M, and Andreeff M
- Subjects
- Animals, Bone and Bones metabolism, Cell Adhesion, Cell Line, Transformed, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Endothelial Cells cytology, Gene Expression Profiling, Humans, Mice, RNA, Messenger metabolism, Signal Transduction, Stromal Cells cytology, Drug Resistance, Neoplasm, Gene Expression Regulation, Leukemic, Integrin alpha4beta1 metabolism, NF-kappa B metabolism, Vascular Cell Adhesion Molecule-1 metabolism
- Abstract
Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-κB signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-κB target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-κB activation via chemical agents or the overexpression of the mutant form of inhibitor κB-α (IκBα) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-κB activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-κB in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-κB activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-κB or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.
- Published
- 2014
- Full Text
- View/download PDF
45. Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease.
- Author
-
Parmar S, Liu X, Tung SS, Robinson SN, Rodriguez G, Cooper LJ, Yang H, Shah N, Yang H, Konopleva M, Molldrem JJ, Garcia-Manero G, Najjar A, Yvon E, McNiece I, Rezvani K, Savoldo B, Bollard CM, and Shpall EJ
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes transplantation, Cell Proliferation, Cell- and Tissue-Based Therapy, Fetal Blood cytology, Graft vs Host Disease pathology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Mice, T-Lymphocytes, Regulatory transplantation, Fetal Blood transplantation, Graft vs Host Disease therapy, T-Lymphocytes, Regulatory cytology, Transplantation, Homologous adverse effects
- Abstract
Background Aims: Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3 × 10⁶ cells), and therefore novel methods of Treg expansion to generate clinically relevant numbers are needed., Methods: Several methodologies are currently being used for ex vivo Treg expansion. We report a new approach to expand Treg from CB and demonstrate their efficacy in vitro by blunting allogeneic mixed lymphocyte reactions and in vivo by preventing GvHD through the use of a xenogenic GvHD mouse model., Results: With the use of magnetic cell sorting, naturally occurring Treg were isolated from CB by the positive selection of CD25⁺ cells. These were expanded to clinically relevant numbers by use of CD3/28 co-expressing Dynabeads and interleukin (IL)-2. Ex vivo-expanded Treg were CD4⁺25⁺ FOXP3⁺127(lo) and expressed a polyclonal T-cell receptor, Vβ repertoire. When compared with conventional T-lymphocytes (CD4⁺25⁻ cells), Treg consistently showed demethylation of the FOXP3 TSDR promoter region and suppression of allogeneic proliferation responses in vitro., Conclusions: In our NOD-SCID IL-2Rγ(null) xenogeneic model of GvHD, prophylactic injection of third-party, CB-derived, ex vivo-expanded Treg led to the prevention of GvHD that translated into improved GvHD score, decreased circulating inflammatory cytokines and significantly superior overall survival. This model of xenogenic GvHD can be used to study the mechanism of action of CB Treg as well as other therapeutic interventions., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
46. CXC chemokine receptor 4 expression, CXC chemokine receptor 4 activation, and wild-type nucleophosmin are independently associated with unfavorable prognosis in patients with acute myeloid leukemia.
- Author
-
Konoplev S, Lin P, Yin CC, Lin E, Nogueras González GM, Kantarjian HM, Andreeff M, Medeiros LJ, and Konopleva M
- Subjects
- Adolescent, Adult, Aged, Chromosome Aberrations, Female, Follow-Up Studies, Gene Expression, Humans, Immunohistochemistry, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Nuclear Proteins metabolism, Nucleophosmin, Phosphorylation, Prognosis, Young Adult, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Nuclear Proteins genetics, Receptors, CXCR4 genetics, Receptors, CXCR4 metabolism
- Abstract
Background: CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation and essential for migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts unfavorable prognosis in patients with acute myeloid leukemia (AML). Nucleophosmin (NPM1) mutation is the most frequent genetic abnormality in patients with AML and predicts a favorable prognosis. In vitro studies have suggested that mutant nucleophosmin (NPM) decreases CXCR4-mediated chemotaxis by downregulating CXCR4, thereby linking the NPM and CXCR4 pathways., Patients and Methods: In a group of 117 untreated adults with AML, we used immunohistochemistry to assess bone marrow specimens for CXCR4 and phosphorylated CXCR4 (pCXCR4) expression. All cases also were analyzed for NPM1 mutations using polymerase chain reaction-based methods., Results: CXCR4 expression was detected in 75 patients (64%), and pCXCR4 expression was detected in 31 patients (26%). NPM1 mutations were detected in 63 patients (54%). NPM1 mutations did not correlate with CXCR4 (P = .212) or pCXCR4 (P = .355) expression. The median 5-year overall survival was 27% (95% confidence interval, 19-36), with a median follow-up of 8 months (95% confidence interval, 6-15). In a multivariate Cox proportional hazards model, reduced overall and progression-free survival rates were associated with a history of antecedent hematologic disorder, failure to achieve complete remission, thrombocytopenia, unfavorable cytogenetics, CXCR4 expression, and wild-type NPM1. pCXCR4 expression was independently associated with shorter progression-free survival., Conclusions: There is no correlation between NPM1 mutations and CXCR4 or pCXCR4 expression, suggesting that the CXCR4 and NPM pathways act independently in adult AML., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
47. Asparaginase unveils glutamine-addicted AML.
- Author
-
Samudio I and Konopleva M
- Subjects
- Animals, Female, Humans, Male, Glutamine antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy
- Abstract
In this issue of Blood, Willems et al describe the dependence of acute myeloid leukemia (AML) cells on glutamine for maintaining protein synthesis downstream of mammalian target of rapamycin (mTOR) and show that the enzyme asparaginase can be used to target this dependence. Using various AML cell lines, primary samples, and CD341 stem cells from healthy donors, the authors support the notion that asparaginase may offer a therapeutic benefit in AML—not from its well-known enzymatic activity, but from its “off-target” effects on glutamine levels that result in inhibition of downstream mTOR signaling, inhibition of protein synthesis, and ultimately loss of viability.
- Published
- 2013
- Full Text
- View/download PDF
48. BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells.
- Author
-
Beurlet S, Omidvar N, Gorombei P, Krief P, Le Pogam C, Setterblad N, de la Grange P, Leboeuf C, Janin A, Noguera ME, Hervatin F, Sarda-Mantel L, Konopleva M, Andreeff M, Tu AW, Fan AC, Felsher DW, Whetton A, Pla M, West R, Fenaux P, Chomienne C, and Padua RA
- Subjects
- Animals, Antigens, Ly metabolism, Cell Lineage, Cell Membrane metabolism, Cell Proliferation, Cell Transformation, Neoplastic, Cell Transplantation, Disease Models, Animal, Flow Cytometry, Gene Expression Regulation, Leukemic, MAP Kinase Signaling System, Membrane Proteins metabolism, Mice, Mice, Transgenic, Mitochondria metabolism, Piperazines pharmacology, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Proto-Oncogene Proteins c-kit metabolism, Stem Cells cytology, Biphenyl Compounds pharmacology, Leukemia, Myeloid, Acute metabolism, Nitrophenols pharmacology, Proto-Oncogene Proteins c-bcl-2 metabolism, Sulfonamides pharmacology, ras Proteins metabolism
- Abstract
Myelodysplastic syndrome (MDS) transforms into an acute myelogenous leukemia (AML) with associated increased bone marrow (BM) blast infiltration. Using a transgenic mouse model, MRP8[NRASD12/hBCL-2], in which the NRAS:BCL-2 complex at the mitochondria induces MDS progressing to AML with dysplastic features, we studied the therapeutic potential of a BCL-2 homology domain 3 mimetic inhibitor, ABT-737. Treatment significantly extended lifespan, increased survival of lethally irradiated secondary recipients transplanted with cells from treated mice compared with cells from untreated mice, with a reduction of BM blasts, Lin-/Sca-1(+)/c-Kit(+), and progenitor populations by increased apoptosis of infiltrating blasts of diseased mice assessed in vivo by technicium-labeled annexin V single photon emission computed tomography and ex vivo by annexin V/7-amino actinomycin D flow cytometry, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, caspase 3 cleavage, and re-localization of the NRAS:BCL-2 complex from mitochondria to plasma membrane. Phosphoprotein analysis showed restoration of wild-type (WT) AKT or protein kinase B, extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase patterns in spleen cells after treatment, which showed reduced mitochondrial membrane potential. Exon specific gene expression profiling corroborates the reduction of leukemic cells, with an increase in expression of genes coding for stem cell development and maintenance, myeloid differentiation, and apoptosis. Myelodysplastic features persist underscoring targeting of BCL-2-mediated effects on MDS-AML transformation and survival of leukemic cells.
- Published
- 2013
- Full Text
- View/download PDF
49. Outcome after failure of second generation tyrosine kinase inhibitors treatment as first-line therapy for patients with chronic myeloid leukemia.
- Author
-
Eghtedar A, Kantarjian H, Jabbour E, O'Brien S, Burton E, Garcia-Manero G, Verstovsek S, Ravandi F, Borthakur G, Konopleva M, Quintas-Cardama A, and Cortes J
- Subjects
- Adult, Aged, Aged, 80 and over, Benzamides adverse effects, Drug Resistance, Neoplasm, Female, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Piperazines adverse effects, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Treatment Outcome, Young Adult, Benzamides therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use
- Abstract
Introduction: The outcome of patients with CML who discontinue 2G-TKI initial therapy is unknown. We analyzed the characteristics of patients in whom treatment with first-line 2G-TKIs had failed., Patients and Methods: A total of 218 patients with CML were treated with dasatinib (n = 101) or nilotinib (n = 117; 12 in AP). After a median follow-up of 23 months, 40 patients (18%) discontinued therapy: 25 initially treated with nilotinib (21% of all treated with nilotinib; 6 treated in AP) and 15 (15%) initially treated with dasatinib. Median age of the patients was 47 (range, 19-79) years, and they had received therapy for a median of 8 (range, 0-62) months., Results: Reasons for treatment discontinuation include: toxicity, 16 patients; resistance in CP, 5 patients; transformation to blast phase, 4 patients (2 treated in AP); and other reasons, 15 patients. Subsequent treatment was imatinib in 11 patients, nilotinib in 7, dasatinib in 4, ponatinib in 2, chemotherapy plus dasatinib in 3, stem cell transplant in 2, bafetinib in 1, and unknown or none in 8 patients. A complete cytogenetic response was achieved in 19 patients, including 17 with major molecular response. Fourteen of the patients who achieved a complete molecular response or major molecular response with subsequent TKIs were in CP at the time of 2G-TKI discontinuation., Conclusion: We conclude that treatment failure after first-line therapy with 2G-TKIs is mostly associated with toxicity or patient preference, and these patients respond well to alternative TKIs., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
50. Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment.
- Author
-
Battula VL, Chen Y, Cabreira Mda G, Ruvolo V, Wang Z, Ma W, Konoplev S, Shpall E, Lyons K, Strunk D, Bueso-Ramos C, Davis RE, Konopleva M, and Andreeff M
- Subjects
- Animals, Bone Marrow metabolism, Bone Marrow pathology, Bone Marrow Cells metabolism, Cell Cycle genetics, Cell Proliferation, Cell Separation, Chemokine CXCL12 metabolism, Down-Regulation genetics, Gene Knockdown Techniques, Humans, Leptin metabolism, Leukemia pathology, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Mesenchymal Stem Cells metabolism, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Adipocytes pathology, Bone Marrow Transplantation, Cell Differentiation, Connective Tissue Growth Factor metabolism, Leukemia therapy, Mesenchymal Stem Cells pathology
- Abstract
Mesenchymal stromal cells (MSCs) are a major component of the leukemia bone marrow (BM) microenvironment. Connective tissue growth factor (CTGF) is highly expressed in MSCs, but its role in the BM stroma is unknown. Therefore, we knocked down (KD) CTGF expression in human BM-derived MSCs by CTGF short hairpin RNA. CTGF KD MSCs exhibited fivefold lower proliferation compared with control MSCs and had markedly fewer S-phase cells. CTGF KD MSCs differentiated into adipocytes at a sixfold higher rate than controls in vitro and in vivo. To study the effect of CTGF on engraftment of leukemia cells into BM, an in vivo model of humanized extramedullary BM (EXM-BM) was developed in NOD/SCID/IL-2rg(null) mice. Transplanted Nalm-6 or Molm-13 human leukemia cells engrafted at a threefold higher rate in adipocyte-rich CTGF KD MSC-derived EXM-BM than in control EXM-BM. Leptin was found to be highly expressed in CTGF KD EXM-BM and in BM samples of patients with acute myeloid and acute lymphoblastic leukemia, whereas it was not expressed in normal controls. Given the established role of the leptin receptor in leukemia cells, the data suggest an important role of CTGF in MSC differentiation into adipocytes and of leptin in homing and progression of leukemia.
- Published
- 2013
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.