30 results on '"William G. Wierda"'
Search Results
2. RPPA-based proteomics recognizes distinct epigenetic signatures in chronic lymphocytic leukemia with clinical consequences
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Fieke W Hoff, Eveline S. J. M. de Bont, Kevin Ruiz, Endurance Toro, Anneke D. van Dijk, Ti’ara L. Griffen, William G. Wierda, James W. Lillard, Steven M. Kornblau, Peter P. Ruvolo, Jan A. Burger, and Yihua Qiu
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Oncology ,Cancer Research ,medicine.medical_specialty ,Predictive marker ,biology ,business.industry ,Chronic lymphocytic leukemia ,EZH2 ,Reverse phase protein lysate microarray ,Hematology ,medicine.disease ,hemic and lymphatic diseases ,Internal medicine ,medicine ,biology.protein ,Bruton's tyrosine kinase ,Epigenetics ,Trisomy ,business ,IGHV@ - Abstract
The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance.
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- 2021
3. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations
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Davide Rossi, Ritsuro Suzuki, Xavier Badoux, Eduardo Cervera Ceballos, Florence Cymbalista, Alexander Egle, Virginia Abello, Hoa T. T. Tran, Peter Hillmen, Stephen P. Mulligan, Jennifer R. Brown, William G. Wierda, Stephan Stilgenbauer, Yair Herishanu, Teoman Soysal, Andy C. Rawstron, Colin P. Diong, Carsten Utoft Niemann, Shang Ju Wu, Paolo Ghia, Carolyn Owen, Wierda, W. G., Rawstron, A., Cymbalista, F., Badoux, X., Rossi, D., Brown, J. R., Egle, A., Abello, V., Cervera Ceballos, E., Herishanu, Y., Mulligan, S. P., Niemann, C. U., Diong, C. P., Soysal, T., Suzuki, R., Tran, H. T. T., Wu, S. -J., Owen, C., Stilgenbauer, S., Ghia, P., and Hillmen, P.
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Chronic lymphocytic leukaemia ,Cancer Research ,medicine.medical_specialty ,Consensus ,Neoplasm, Residual ,business.industry ,Chronic lymphocytic leukemia ,MEDLINE ,Review Article ,Hematology ,Disease ,Residual ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Minimal residual disease ,Clinical trial ,Medical research ,Oncology ,Chemoimmunotherapy ,Practice Guidelines as Topic ,Humans ,Medicine ,business ,Intensive care medicine ,Disease burden - Abstract
Assessment of measurable residual disease (often referred to as “minimal residual disease”) has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.
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- 2021
4. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen for chronic lymphocytic leukemia (CLL) with mutated IGHV and without TP53 aberrations
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Zeev Estrov, Prithviraj Bose, Varsha Gandhi, Jan A. Burger, Xuemei Wang, Naveen Garg, Rashmi Kanagal-Shamanna, Naveen Pemmaraju, Philip A. Thompson, Ana Ayala, Hagop M. Kantarjian, Koji Sasaki, Keyur P. Patel, Tapan M. Kadia, Alessandra Ferrajoli, Susan O'Brien, Elias Jabbour, Gautam Borthakur, Koichi Takahashi, Marina Konopleva, Wanda Lopez, Michael J. Keating, Wei Wang, William G. Wierda, Nitin Jain, Jeffrey L. Jorgensen, William Plunkett, and Sa Wang
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cyclophosphamide ,Chronic lymphocytic leukemia ,Immunoglobulin Variable Region ,Neutropenia ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Obinutuzumab ,Chemoimmunotherapy ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Aged ,business.industry ,Adenine ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Fludarabine ,Survival Rate ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Mutation ,Female ,Tumor Suppressor Protein p53 ,Immunoglobulin Heavy Chains ,business ,IGHV@ ,Vidarabine ,Follow-Up Studies ,medicine.drug - Abstract
Chemoimmunotherapy with combined fludarabine, cyclophosphamide and rituximab (FCR) has been an effective treatment for patients with chronic lymphocytic leukemia (CLL). We initiated a phase II trial for previously untreated patients with CLL with mutated IGHV and absence of del(17p)/TP53 mutation. Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for three cycles. Patients who achieved complete remission (CR)/CR with incomplete count recvoery (CRi) with marrow undetectable measurable residual disease (U-MRD) received additional nine cycles of ibrutinib with three cycles of obinutuzumab; all others received nine additional cycles of ibrutinib and obinutuzumab. Patients in marrow U-MRD remission after cycle 12 discontinued all treatment, including ibrutinib. Forty-five patients were treated. The median follow-up is 41.3 months. Among the total 45 treated patients, after three cycles, 38% achieved CR/CRi and 87% achieved marrow U-MRD. After cycle 12, the corresponding numbers were 67% and 91%, respectively. Overall, 44/45 (98%) patients achieved marrow U-MRD as best response. No patient had CLL progression. The 3-year progression-free survival (PFS) and overall survival (OS) were 98% and 98%, respectively. Per trial design, all patients who completed cycle 12 discontinued ibrutinib, providing for a time-limited therapy. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% patients, respectively. The iFCG regimen with only 3 cycles of chemotherapy is an effective, time-limited regimen for patients with CLL with mutated IGHV and without del(17p)/TP53 mutation.
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- 2021
5. Autologous CD33-CAR-T cells for treatment of relapsed/refractory acute myelogenous leukemia
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Timothy A. Chan, Harjeet Singh, Emily Jones, Francesco Paolo Tambaro, Tapan M. Kadia, Kris M. Mahadeo, Guillermo Garcia-Manero, Shah Rutul R, Courtney D. DiNardo, William G. Wierda, Philip A. Thompson, Naval Daver, and Michael Rytting
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Adult ,Male ,Cancer Research ,Letter ,Adolescent ,Sialic Acid Binding Ig-like Lectin 3 ,CD33 ,Diseases ,Autoantigens ,Immunotherapy, Adoptive ,Acute myeloid leukaemia ,Young Adult ,Myelogenous ,Text mining ,medicine ,Humans ,Aged ,Salvage Therapy ,business.industry ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Myeloid, Acute ,Leukemia ,Oncology ,Drug Resistance, Neoplasm ,Relapsed refractory ,Cancer research ,Female ,Neoplasm Recurrence, Local ,Car t cells ,business ,Follow-Up Studies - Published
- 2021
6. Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality
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Ghayas C. Issa, Koichi Takahashi, Prithviraj Bose, Elias Jabbour, Steven M. Kornblau, Hagop M. Kantarjian, Jorge E. Cortes, William G. Wierda, Zeev Estrov, Maro Ohanian, Nitin Jain, Naval Daver, Srdan Verstovsek, Naveen Pemmaraju, Yesid Alvarado, Gautam Borthakur, Jing Ning, Alessandra Ferrajoli, Courtney D. DiNardo, Guillermo Garcia-Manero, Lianchun Xiao, Farhad Ravandi, Kiran Naqvi, M. Andreeff, and Tapan M. Kadia
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Daunorubicin ,medicine.medical_treatment ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Adverse effect ,Chemotherapy ,business.industry ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cytarabine ,business ,Febrile neutropenia ,medicine.drug - Abstract
CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m2 on days 1, 3, and 5. Once safety was established, a 100 units/m2 arm was opened. Fifty-six patients were enrolled, 16, 24, and 16 in the 50, 75, and 100 units/m2 arms, respectively. The composite complete remission rate (complete remission + complete remission with incomplete blood count recovery) was lowest with 50 units/m2 (19%) compared with 75 units/m2 (38%) and 100 units/m2 (44%) (P = 0.35). The 50 units/m2 arm had a median OS of 4.3 months, compared with 8.6 and 6.2 months for the 75 and 100 units/m2 respectively (P = 0.04). Nonhematologic grade 3/4 treatment-emergent adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%). CPX-351 at 75 units/m2 has favorable safety and efficacy for AML patients at high risk of induction mortality with some tolerating the standard dose of 100 units/m2.
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- 2020
7. The BET inhibitor GS-5829 targets chronic lymphocytic leukemia cells and their supportive microenvironment
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Elisa Ten Hacken, Zeev Estrov, Kapil N. Bhalla, Astrid Clarke, Mariela Sivina, Philip A. Thompson, Michael J. Keating, Ekaterina Kim, William G. Wierda, Nitin Jain, Alessandra Ferrajoli, and Jan A. Burger
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0301 basic medicine ,Cancer Research ,Chronic lymphocytic leukemia ,Syk ,Antineoplastic Agents ,Apoptosis ,BET Inhibitor GS-5829 ,Article ,BET inhibitor ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Tumor Microenvironment ,medicine ,Humans ,Bruton's tyrosine kinase ,Enzyme Inhibitors ,Protein kinase B ,Cells, Cultured ,Cell Proliferation ,biology ,Chemistry ,Proteins ,Drug Synergism ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Ibrutinib ,Cancer research ,biology.protein ,Idelalisib ,Signal Transduction - Abstract
Despite major improvements in treatment outcome with novel targeted therapies, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, chronic lymphocytic leukemia (CLL) remains incurable in the majority of patients. Activation of PI3K, NF-κB, and/or MYC has been linked to residual disease and/or resistance in ibrutinib-treated patients. These pathways can be targeted by inhibitors of bromodomain and extra-terminal (BET) proteins. Here we report about the preclinical activity of GS-5829, a novel BET inhibitor, in CLL. GS-5829 inhibited CLL cell proliferation and induced leukemia cell apoptosis through deregulation of key signaling pathways, such as BLK, AKT, ERK1/2, and MYC. IκBα modulation indicates that GS-5829 also inhibited NF-κB signaling. GS-5829-induced apoptosis resulted from an imbalance between positive (BIM) and negative regulators (BCL-XL) of the intrinsic apoptosis pathway. The anti-leukemia activity of GS-5829 increased synergistically in combinations with B cell receptor signaling inhibitors, the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, and the SYK inhibitor entospletinib. In co-cultures that mimic the lymph node microenvironment, GS-5829 inhibited signaling pathways within nurselike cells and their growth, indicating that BET inhibitors also can target the supportive CLL microenvironment. Collectively, these data provide a rationale for the clinical evaluation of BET inhibitors in CLL.
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- 2019
8. Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells
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Rong Chen, Yuling Chen, Ping Xiong, Daniella Zheleva, David Blake, Michael J. Keating, William G. Wierda, and William Plunkett
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Cancer Research ,Sulfonamides ,Adenosine ,Apoptosis ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Lymphocytic, Chronic, B-Cell ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,hemic and lymphatic diseases ,Roscovitine ,Tumor Microenvironment ,Humans ,Myeloid Cell Leukemia Sequence 1 Protein ,Apoptosis Regulatory Proteins ,Protein Kinase Inhibitors - Abstract
Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.
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- 2021
9. Activation and expansion of T-follicular helper cells in chronic lymphocytic leukemia nurselike cell co-cultures
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Alicia M. Vaca, Nikolaos Ioannou, Mariela Sivina, Elisavet Vlachonikola, Karen Clise-Dwyer, Ekaterina Kim, Dan Li, Qing Ma, Alessandra Ferrajoli, Zeev Estrov, William G. Wierda, Piers E. M. Patten, Alan G. Ramsay, and Jan A. Burger
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Receptors, CXCR5 ,Cancer Research ,Oncology ,T Follicular Helper Cells ,Tumor Microenvironment ,Humans ,Hematology ,T-Lymphocytes, Helper-Inducer ,Leukemia, Lymphocytic, Chronic, B-Cell ,Coculture Techniques - Abstract
Interactions between chronic lymphocytic leukemia (CLL) cells and T-cell subsets in the lymph node microenvironment are thought to play a central role in disease biology. To study these interactions in a model of the CLL lymph node microenvironment, we characterized T-cell subsets in CLL nurselike cell (NLC) co-cultures. We focused on T-follicular helper (Tfh) cells, which are characterized by CXCR5 expression and localization to B-cell follicles. In co-cultures from 28 different CLL patients, we detected an expansion of Tfh cells based on PD-1, BCL6, and ICOS expression, with increased IL-21 and downmodulated CD40L surface expression. Regulatory T cells (Treg), which promote immune tolerance, also expanded in NLC co-cultures. T-cell receptor (TR) gene repertoire analyses confirmed the clonal expansion of CD4
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- 2021
10. Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia
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William G. Wierda, Shuxing Zhang, Qun Qin, Mingzhao Zhu, Rong Chen, William Plunkett, Yuling Chen, Wesley Skillern, Kenneth G. Hull, Rajan Chaudhari, Daniel Romo, and Omar Robles
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Male ,Models, Molecular ,0301 basic medicine ,Cancer Research ,Protein Conformation ,Chronic lymphocytic leukemia ,Apoptosis ,Context (language use) ,Plasma protein binding ,Article ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Humans ,Initiation factor ,RNA, Messenger ,Aged ,Aged, 80 and over ,Sulfonamides ,Chemistry ,Drug Synergism ,Translation (biology) ,Hematology ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Gene Expression Regulation, Neoplastic ,Thiazoles ,Leukemia ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Protein Biosynthesis ,030220 oncology & carcinogenesis ,eIF4A ,Eukaryotic Initiation Factor-4A ,Cancer research ,Epoxy Compounds ,Myeloid Cell Leukemia Sequence 1 Protein ,Drug Therapy, Combination ,Female ,Macrolides ,Follow-Up Studies - Abstract
The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL.
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- 2019
11. CXCL13 plasma levels function as a biomarker for disease activity in patients with chronic lymphocytic leukemia
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Jan A. Burger, Zeev Estrov, Nicholas Chiorazzi, Shih-Shih Chen, Lianchun Xiao, Alicia Vaca, Michael J. Keating, Nitin Jain, Mariela Sivina, Alessandra Ferrajoli, William G. Wierda, Ekaterina Kim, and Xuelin Huang
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0301 basic medicine ,Male ,Cancer Research ,Chronic lymphocytic leukemia ,Severity of Illness Index ,CXCR5 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Piperidines ,immune system diseases ,In vivo ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,CXCL13 ,Receptor ,Aged ,Retrospective Studies ,business.industry ,Adenine ,Germinal center ,Hematology ,medicine.disease ,Prognosis ,Chemokine CXCL13 ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Rate ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Cancer research ,Female ,business ,Follow-Up Studies - Abstract
The chemoattractant CXCL13 organizes the cellular architecture of B-cell follicles and germinal centers. During adaptive immune responses, CXCL13 plasma concentrations transiently increase and function as a biomarker for normal germinal center activity. Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR5, the receptor for CXCL13, and proliferate in pseudofollicles within secondary lymphoid organs (SLO). Given the morphologic and functional similarities between normal and CLL B-cell expansion in SLO, we hypothesized that CXCL13 plasma concentrations would correlate with CLL disease activity and progression. We analyzed CXCL13 plasma concentrations in 400 CLL patients and correlated the findings with other prognostic markers, time to treatment (TTT), CCL3 and CCL4 plasma concentrations, and in vivo CLL cell proliferation. We found that CXCL13 plasma concentrations were higher in CLL patients with active and advanced stage disease, resulting in a significantly shorter TTT. Accordingly, high CXCL13 levels correlated with other markers of disease activity and CCL3 levels. Higher CLL cell birth rates in vivo also associated with higher CXCL13 plasma concentrations. Interestingly, elevated CXCL13 plasma levels normalized during ibrutinib therapy, and increased in ibrutinib resistance patients. Collectively, these studies emphasize the importance of CXCL13 in crosstalk between CLL cells and the SLO microenvironment.
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- 2020
12. Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality
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Ghayas C, Issa, Hagop M, Kantarjian, Lianchun, Xiao, Jing, Ning, Yesid, Alvarado, Gautam, Borthakur, Naval, Daver, Courtney D, DiNardo, Elias, Jabbour, Prithviraj, Bose, Nitin, Jain, Tapan M, Kadia, Kiran, Naqvi, Naveen, Pemmaraju, Koichi, Takahashi, Srdan, Verstovsek, Micheal, Andreeff, Steven M, Kornblau, Zeev, Estrov, Alessandra, Ferrajoli, Guillermo, Garcia-Manero, Maro, Ohanian, William G, Wierda, Farhad, Ravandi, and Jorge E, Cortes
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Aged, 80 and over ,Male ,Daunorubicin ,Remission Induction ,Cytarabine ,Kaplan-Meier Estimate ,Middle Aged ,Prognosis ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Risk Factors ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Female ,Biomarkers ,Aged - Abstract
CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m
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- 2020
13. Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies
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Jan A. Burger, Philip A. Thompson, Gautam Borthakur, Zeev Estrov, Naval Daver, Courtney D. DiNardo, Paolo Strati, Tapan M. Kadia, Christine B. Peterson, Alessandra Ferrajoli, Michael J. Keating, Elias Jabbour, William G. Wierda, Nitin Jain, Jeff L. Jorgensen, and Susan O'Brien
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Neoplasm, Residual ,0302 clinical medicine ,Bone Marrow ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Prospective Studies ,Prospective cohort study ,Aged, 80 and over ,FCR ,Hematology ,Middle Aged ,3. Good health ,Leukemia ,MRD ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Immunotherapy ,Rituximab ,Vidarabine ,Adult ,medicine.medical_specialty ,End of therapy ,First line ,IGHV mutation status ,Disease-Free Survival ,Article ,03 medical and health sciences ,Chemoimmunotherapy ,Internal medicine ,medicine ,Humans ,Chronic Lymphocytic Leukemia ,In patient ,Cyclophosphamide ,Aged ,business.industry ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Minimal residual disease ,body regions ,030104 developmental biology ,Bone marrow ,business ,CLL - Abstract
Achieving undetectable MRD (U-MRD) status after chemoimmunotherapy predicts longer progression-free and overall survival. The predictive factors and timing of relapse in patients with U-MRD and value of interim MRD analysis are ill-defined. This was a prospective study of 289 patients with CLL treated first-line with FCR. MRD analysis was performed after course 3 (C3) and at end-of-therapy (EOT) in bone marrow using 4-color flow cytometry (sensitivity 10−4). Eighteen percent of patients had U-MRD after C3 and 48% at EOT. U-MRD status at EOT was associated with longer PFS (median NR vs 38mo, p1%) after C3 predicted greater likelihood of U-MRD status at EOT (64% vs. 9%, p1% after C3 (median 73mo vs 41mo, p
- Published
- 2018
14. Sustained long-lasting responses after lenalidomide discontinuation in patients with chronic lymphocytic leukemia
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Zeev Estrov, Paolo Strati, Michael J. Keating, Christina Hinojosa, Susan O'Brien, Katy Rezvani, William G. Wierda, Nitin Jain, Hagop M. Kantarjian, Jan A. Burger, Alessandra Ferrajoli, and Philip A. Thompson
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Salvage therapy ,Antineoplastic Agents ,Ofatumumab ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Obinutuzumab ,medicine ,Humans ,Lenalidomide ,health care economics and organizations ,Aged ,Aged, 80 and over ,Response rate (survey) ,business.industry ,Venetoclax ,Hematology ,Middle Aged ,Leukemia, Lymphocytic, Chronic, B-Cell ,Discontinuation ,Clinical trial ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Family medicine ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Introduction. The clinical benefits of lenalidomide in patients with CLL are well established. Lenalidomide inhibits CLL-cell proliferation, enhances T-cell synapse formation and CD154 expression, and modulates the leukemia cell microenvironment. Although clinically beneficial, side effects such as infection due to myelosuppression, diarrhea, peripheral neuropathy, and skin rash occasionally impose treatment discontinuation. Because lenalidomide reduces PD-1 and PDL-1 expression and induces CLL-T-cell synapse formation, we sought to determine whether, similar to checkpoint inhibitors, the clinical effect of lenalidomide persists after treatment discontinuation. Methods. We analyzed the clinical characteristics of patients with CLL who were enrolled in clinical trials with lenalidomide at the MD Anderson Cancer Center (MDACC) and discontinued lenalidomide because of toxicity. In these frontline or salvage trials, lenalidomide was administered as a single agent or in combination with anti-CD20 monoclonal antibodies. Time to next treatment (TTNT) was calculated from the date of lenalidomide discontinuation to the date of subsequent treatment or last follow-up, and a univariate analysis and a log-rank test was performed. Results. Lenalidomide was discontinued due to toxicity in 43 of 208 patients treated. The median age of those patients was 66 (range, 42-83); 22 (52%) patients were men; 40% had advanced Rai stage, 52% had β2M of ≥4 mg/L; 57% had unmutated IGHV , and 21% had unfavorable cytogenetic abnormalities [including del(11q) or del(17p)]. Fourteen patients (31%) received single agent lenalidomide and 29 patients (69%) received lenalidomide in combination with an anti-CD20 monoclonal antibody (rituximab or ofatumumab). Thirty-eight (88%) patients received lenalidomide as frontline therapy and 5 (22%) as salvage therapy. In 2 patients lenalidomide was discontinued 2 and 3 months after treatment initiation because of grade > 3 infectious complications, and subsequent treatment started before response assessment; these two patients were included in the survival analysis, but not in the response assessment. In the 41 evaluable patients, the overall response rate (ORR) was 71%; complete remission (CR) rate was 24% with undetectable minimal residual disease in 2 of those patients (5%), and partial response (PR) rate was 46%. Median treatment duration was 11 months (range, 1-39 months) and 8 patients had Among all 43 patients, the median TTNT was 40 months (range, 1-96 months). Subsequent lines of therapy included BTK or PI3K inhibitors (13 patients), ofatumumab, obinutuzumab or rituximab with methylprednisolone (7 patients), chemoimmunotherapy (3 patients), or venetoclax (1 patient). The vast majority of patients responded to subsequent lines of therapy with an ORR of 95% and a CR rate of 45%. A univariate analysis showed that a long TTNT was associated with a clinical response (CR or PR) at time of treatment discontinuation ( P = 0.01) and/or ≥ 2 months treatment duration ( P =0.007) (Figure). The median overall survival of the 43 evaluated patients has not been reached at a median follow-up of 40 months (10-108 months) and 9 patients (21%) had died. Conclusion. CLL patients whose lenalidomide treatment was discontinued due to toxicity experienced a long TTNT with a median duration of more than 40 months. These patients also showed a high response rate to subsequent lines of therapy with responses seen in 95% of patients. These findings suggest that the immunomodulatory effects of lenalidomide persist after treatment discontinuation. Correlative laboratory studies to determine whether lenalidomide induces a checkpoint inhibitor-like effect are ongoing. Disclosures Wierda: Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Karyopharm: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; The University of Texas MD Anderson Cancer Center: Employment; Kite: Research Funding; Juno: Research Funding; Acerta: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Jain: Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Research Funding; Pharmacyclics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Thompson: Pharmacyclics: Honoraria, Membership on an entity9s Board of Directors or advisory committees. O9Brien: Acerta: Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Janssen: Consultancy; Aptose Biosciences, Inc.: Consultancy; Sunesis: Consultancy; ProNAI: Other: Research Support: Honorarium, Research Funding; Amgen: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy, Research Funding; Alexion: Consultancy; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Celgene: Consultancy; GSK: Consultancy; Astellas: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; CLL Global Research Foundation: Membership on an entity9s Board of Directors or advisory committees; Vaniam Group LLC: Consultancy. Kantarjian: Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Burger: Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding.
- Published
- 2018
15. Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia
- Author
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Elizabeth Murphy, Clive S. Zent, Claire L. Emson, Marc K. Hellerstein, Nicholas Chiorazzi, Donna Neuberg, Robert A. Redd, Neil E. Kay, Laura Z. Rassenti, K Li, Thomas J. Kipps, Kanti R. Rai, Jennifer R. Brown, John C. Byrd, Gregory M. Hayes, William G. Wierda, Andrew W. Greaves, Jaqueline C. Barrientos, Scott M. Turner, and C McConnel
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Article ,03 medical and health sciences ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,Prospective Studies ,Prospective cohort study ,Survival rate ,Aged ,Cell Proliferation ,Neoplasm Staging ,Aged, 80 and over ,Hematology ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Lymphoma ,Survival Rate ,Leukemia ,030104 developmental biology ,Immunology ,Mutation ,Disease Progression ,Female ,IGHV@ ,business ,Follow-Up Studies - Abstract
The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P
- Published
- 2017
16. Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199)
- Author
-
Kumudha Balakrishnan, Howard M. Stern, Varsha Gandhi, Susan O'Brien, William G. Wierda, Jeffery L. Kutok, Viralkumar Patel, Aloke Sarkar, Mark Douglas, Nitin Jain, Mary Ayers, Thomas T. Tibbitts, Renato Guerrieri, and Ethan Y. Xu
- Subjects
0301 basic medicine ,Cancer Research ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Apoptosis ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Humans ,Medicine ,neoplasms ,Sensitization ,Sulfonamides ,Tumor microenvironment ,business.industry ,Venetoclax ,Drug Synergism ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Isoquinolines ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Duvelisib ,Lymphoma ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Purines ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Apoptosis Regulatory Proteins ,business - Abstract
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.
- Published
- 2016
17. A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials
- Author
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Farhad Ravandi, X. Huang, Ana Alfonso, Sherry Pierce, Zachary S. Bohannan, Srdan Verstovsek, G. Borthakur, Guillermo Montalban-Bravo, Mark Brandt, William G. Wierda, Courtney D. DiNardo, Nitin Jain, E. Jabbour, Hsiang-Chun Chen, Marina Konopleva, Eli Estey, H. Yang, Kiran Naqvi, Naval Daver, Hagop M. Kantarjian, Yesid Alvarado, Jorge E. Cortes, Zeev Estrov, C. E. Bueso-Ramos, G. Garcia-Manero, Naveen Pemmaraju, Troy Sneed, and Tapan M. Kadia
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Azacitidine ,Comorbidity ,Kaplan-Meier Estimate ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,Adverse effect ,Survival rate ,Aged ,Aged, 80 and over ,Chromosome Aberrations ,business.industry ,Myelodysplastic syndromes ,Organ dysfunction ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Clinical trial ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Physical therapy ,Female ,medicine.symptom ,business ,Biomarkers ,Follow-Up Studies ,medicine.drug ,030215 immunology - Abstract
Most clinical trials exclude patients with poor performance or comorbidities. To study whether patients with these characteristics can be treated within a clinical trial, we conducted a study for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with poor performance, organ dysfunction or comorbidities. Primary endpoint was 60-day survival. Study included stopping rules for survival and response. Treatment consisted on a combination of azacitidine and vorinostat. Thirty patients (16 with MDS, 14 with AML) were enrolled. Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. No stopping rules were met. Main adverse events (AEs) were grades 1 and 2 gastrointestinal toxicities. In view of these results, we expanded the study and treated 79 additional patients: 27 with azacitidine (AZA) and 52 with azacitidine and vorinostat (AZA+V). Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rate was 79% (AZA=67%, AZA+V=85%, P=0.07). Median overall survival was 7.6 months (4.5-10.7). Median event-free survival was 4.5 months (3.5-5.6). Main AEs included grades 1 and 2 gastrointestinal toxicities. Our results suggest this subset of patients can be safely treated within clinical trials and derive clinical benefit. Relaxation of standard exclusion criteria may increase the pool of patients likely to benefit from therapy.
- Published
- 2017
18. Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway
- Author
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Elif Gokdemir, Muharrem Muftuoglu, Zeev Estrov, Nobuhiko Imahashi, Philip A. Thompson, Ekaterina Kim, M. Keating, Catherine Sobieski, Hila Shaim, Enli Liu, A. Ferrajoli, Neeraj Jain, May Daher, Elizabeth J. Shpall, David Harris, Abdullah Alsuliman, William G. Wierda, Kayo Kondo, Jan A. Burger, Katy Rezvani, and Rafet Basar
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Male ,STAT3 Transcription Factor ,Cancer Research ,Regulatory B cells ,Chronic lymphocytic leukemia ,Programmed Cell Death 1 Receptor ,Biology ,Pharmacology ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,Article ,Immune tolerance ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,immune system diseases ,PD-L1 ,hemic and lymphatic diseases ,medicine ,Immune Tolerance ,Tumor Microenvironment ,Bruton's tyrosine kinase ,Humans ,Protein Kinase Inhibitors ,Aged ,Tumor microenvironment ,B-Lymphocytes, Regulatory ,Adenine ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,Pyrimidines ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,biology.protein ,Cancer research ,STAT protein ,Pyrazoles ,Female ,Immunosuppressive Agents ,Signal Transduction - Abstract
Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naive chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.
- Published
- 2017
19. Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia
- Author
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Elena Hartmann, Elena Vasyutina, Andreas Rosenwald, Jan A. Burger, Marco Herling, Jorge Boucas, William G. Wierda, Mariela Sivina, Michael J. Keating, and Alexandra Breuer
- Subjects
Cancer Research ,Cell signaling ,Stromal cell ,Transcription, Genetic ,Cell Survival ,Proto-Oncogene Proteins c-jun ,Chronic lymphocytic leukemia ,Bone Marrow Cells ,Cell Communication ,Biology ,Proto-Oncogene Mas ,Downregulation and upregulation ,immune system diseases ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,medicine ,Cluster Analysis ,Humans ,neoplasms ,Regulation of gene expression ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Coculture Techniques ,Transcription Factor AP-1 ,Myeloid Cell Leukemia Sequence 1 Protein ,MicroRNAs ,Leukemia ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Immunology ,Cancer research ,Interleukin-4 ,Bone marrow ,Stromal Cells ,Proto-Oncogene Proteins c-akt ,Proto-Oncogene Proteins c-fos - Abstract
The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined. Bone marrow stromal cells (BMSC) protect CLL cells from apoptosis in a contact-dependent fashion, and have been used for the identification of key pathways such as the CXCR4-CXCL12 axis. To further dissect the molecular impact of BMSC on survival and the molecular activation signature of CLL cells, we co-cultured CLL cells with different BMSC. Gene expression profiling of CLL cells revealed that the lymphoid proto-oncogene TCL1 was among the top genes upregulated in CLL cells by BMSC. TCL1 mRNA and protein upregulation by BMSC was paralleled by decreases of TCL1-interacting FOS/JUN, and confirmed by qRT-PCR, immunoblotting, immunoprecipitations, and flow cytometry. Stroma mediated increases in TCL1 were also associated with decreased levels of TCL1-regulatory micro-RNAs (miR-29b, miR-181b, miR-34b). These findings demonstrate that the microenvironment has a proactive role in the regulation of the known signaling enhancer and pro-survival molecule TCL1 in CLL. This provides a further rationale for therapeutically targeting the cross talk between CLL and BMSC.
- Published
- 2012
20. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration
- Author
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Uma Sinha, Jan A. Burger, Mariela Sivina, Farhad Ravandi, William G. Wierda, Susan O'Brien, Michael J. Keating, Julia Hoellenriegel, Alessandra Ferrajoli, Anjali Pandey, and Greg Coffey
- Subjects
Cancer Research ,Chronic lymphocytic leukemia ,Blotting, Western ,Syk ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Fostamatinib ,Article ,Cell Movement ,hemic and lymphatic diseases ,Cell Adhesion ,Tumor Cells, Cultured ,medicine ,Humans ,Syk Kinase ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,Cyclohexylamines ,Chemistry ,Kinase ,Chemotaxis ,Intracellular Signaling Peptides and Proteins ,breakpoint cluster region ,hemic and immune systems ,Cell migration ,Hematology ,Protein-Tyrosine Kinases ,Flow Cytometry ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Pyrimidines ,Oncology ,Cancer research ,Stromal Cells ,Tyrosine kinase ,medicine.drug - Abstract
Syk is a protein tyrosine kinase that couples B-cell receptor (BCR) activation with downstream signaling pathways, affecting cell survival and proliferation. Moreover, Syk is involved in BCR-independent functions, such as B-cell migration and adhesion. In chronic lymphocytic leukemia (CLL), Syk becomes activated by external signals from the tissue microenvironment, and was targeted in a first clinical trial with R788 (fostamatinib), a relatively nonspecific Syk inhibitor. Here, we characterize the activity of two novel, highly selective Syk inhibitors, PRT318 and P505-15, in assays that model CLL interactions with the microenvironment. PRT318 and P505-15 effectively antagonize CLL cell survival after BCR triggering and in nurse-like cell-co-cultures. Moreover, they inhibit BCR-dependent secretion of the chemokines CCL3 and CCL4 by CLL cells, and leukemia cell migration toward the tissue homing chemokines CXCL12, CXCL13, and beneath stromal cells. PRT318 and P505-15 furthermore inhibit Syk and extracellular signal-regulated kinase phosphorylation after BCR triggering. These findings demonstrate that the selective Syk inhibitors PRT318 and P505-15 are highly effective for inhibition of CLL survival and tissue homing circuits, and support the therapeutic development of these agents in patients with CLL, other B-cell malignancies and autoimmune disorders.
- Published
- 2012
21. HLA homozygosity and haplotype bias among patients with chronic lymphocytic leukemia: implications for disease control by physiological immune surveillance
- Author
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Ruth LaPushin, H. Yang, Simon N. Robinson, Dongxia Xing, William G. Wierda, William K. Decker, Shawndeep Tung, Marcelo Fernandez-Vina, Simrit Parmar, Susan O'Brien, Elizabeth J. Shpall, and Nina Shah
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Human leukocyte antigen ,Internal medicine ,medicine ,Humans ,Immunologic Surveillance ,Aged ,Hematology ,business.industry ,Homozygote ,Haplotype ,Cancer ,Middle Aged ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,Disease control ,Immune surveillance ,Immunosurveillance ,Haplotypes ,Oncology ,Immunology ,Female ,business - Abstract
HLA homozygosity and haplotype bias among patients with chronic lymphocytic leukemia: implications for disease control by physiological immune surveillance
- Published
- 2011
22. A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154
- Author
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M. Keating, Charles E. Prussak, Januario E. Castro, Deepa Sampath, John McMannis, Thomas J. Kipps, Annette Jalayer, R.A. Aguillon, and William G. Wierda
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Genetic enhancement ,Chronic lymphocytic leukemia ,CD40 Ligand ,Article ,Immune system ,immune system diseases ,Chemoimmunotherapy ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,fas Receptor ,CD40 Antigens ,CD154 ,neoplasms ,Aged ,Neoplasm Staging ,Sequence Deletion ,CD40 ,Hematology ,biology ,business.industry ,Genetic Therapy ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,Microscopy, Fluorescence ,Oncology ,Immunology ,biology.protein ,Female ,business ,Chromosomes, Human, Pair 17 - Abstract
Ligation of CD40 on chronic lymphocytic leukemia (CLL) cells induces phenotypic and biochemical changes that facilitate CLL cell-T cell interactions and enhances the sensitivity of CLL cells to clearance by adaptive and innate immune-effector mechanisms. CLL cells can be transduced to express CD40 ligand (CD154) using a replication-defective adenovirus vector, thereby cross-linking CD40 on transduced and non-transduced, bystander CLL cells. In a previous study, patients received infusions of autologous CLL cells, transduced to express murine CD154 (mCD154), which induced anti-leukemic immune responses, but also anti-mCD154 antibodies. In this study, we report a phase I study, in which patients were infused with 1 × 10(8), 3 × 10(8) or 1 × 10(9) autologous CLL cells transduced ex vivo to express ISF35, a humanized, membrane-stable CD154. Infusions were well tolerated and consistently followed by reductions in blood lymphocyte counts and lymphadenopathy. After infusion, circulating CLL cells had enhanced or de novo expression of CD95, DR5, p73 and Bid, which enhanced their susceptibility to death-receptor-mediated or drug-induced apoptosis, including CLL cells with deletions at 17p13.1 (del(17p)). Two patients who had CLL with del(17p) had subsequent chemoimmunotherapy and responded well to treatment. In summary, infusions of autologous, ISF35-transduced CLL cells were well tolerated, had biological and clinical activity, and might enhance the susceptibility of CLL cells with del(17p) to chemoimmunotherapy.
- Published
- 2010
23. Outcomes for patients with chronic lymphocytic leukemia and acute leukemia or myelodysplastic syndrome
- Author
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Guillermo Garcia-Manero, Francesco Paolo Tambaro, Alessandra Ferrajoli, Jan A. Burger, Hagop M. Kantarjian, Stefan Faderl, Michael J. Keating, Susan O'Brien, Xuemei Wang, William G. Wierda, Kim Anh Do, and Sherry Pierce
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Chronic lymphocytic leukemia ,Karyotype ,Article ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,neoplasms ,Aged ,Retrospective Studies ,Acute leukemia ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Regimen ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Immunology ,Female ,business - Abstract
Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2 (0-9) and 1 (0-8), respectively; the most common regimen was purine analog combined with alkylating agent±CD20 monoclonal antibody. Twelve cases had no prior CLL treatment. Among 38 cases with AL, 33 had acute myelogenous leukemia (AML), 3 had acute lymphoid leukemia (ALL; 1 Philadelphia chromosome positive), 1 had biphenotypic and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, and intermediate risk in 7 patients. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all International Prognostic Scoring System (IPSS) were represented; karyotype was unfavorable in 36, intermediate in 6 and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher risk IPSS, poor-risk karyotype and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were very poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed.
- Published
- 2015
24. T cell activation following infection of primary follicle center lymphoma B cells with adenovirus encoding CD154
- Author
-
William G. Wierda, Izidore S. Lossos, M. J. Cantwell, Thomas J. Kipps, and Ronald Levy
- Subjects
Cancer Research ,Adoptive cell transfer ,Lymphoma, B-Cell ,T-Lymphocytes ,T cell ,CD40 Ligand ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Adenoviridae ,Mice ,Interleukin 21 ,NK-92 ,immune system diseases ,parasitic diseases ,medicine ,Animals ,Humans ,CD154 ,Antigen-presenting cell ,CD40 ,hemic and immune systems ,Hematology ,Virology ,Molecular biology ,Phenotype ,surgical procedures, operative ,medicine.anatomical_structure ,Oncology ,biology.protein ,Lymph Nodes ,Lymphocyte Culture Test, Mixed ,CD5 ,Cell Division ,HeLa Cells - Abstract
Purified, high-titer adenovirus encoding murine CD154 (Ad-CD154) or human CD154 (Ad-hCD154) was used to infect lymph node cells isolated from patients with follicle center lymphoma. Infection of lymphoma B cells with Ad-CD154 at a multiplicity of infection (MOI) ratio of 100 or higher resulted in high-level transgene expression. Additionally, upon infection of lymphoma B cells, only Ad-CD154 resulted in surface expression of CD154, despite similar, high-level expression of either human or mouse CD154 by HeLa cells infected with Ad-hCD154 or Ad-CD154, respectively. Moreover, infection of lymphoma B cells with Ad-CD154, but not Ad-hCD154 or adenovirus encoding Eschericheria coli beta-galactosidase (Ad-LacZ), induced the neoplastic B cells to express higher levels of immune co-stimulatory molecules that are required for proficient presentation of antigen to T cells. Consistent with this, we found that Ad-CD154 infected lymphoma B cells could stimulate T cells to proliferate or produce interferon-gamma in allogeneic or autologous mixed lymphocyte interactions. We conclude that lymphoma B cells can be infected with Ad-CD154 and that this significantly enhances their recognition by allogeneic or autologous T cells. As such, Ad-CD154-transduced lymphoma B cells may have potential for the active immune therapy of patients with follicle center lymphoma.
- Published
- 2001
25. Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP
- Author
-
Michael J. Keating, Stefan Koehrer, and William G. Wierda
- Subjects
Agonist ,Thrombopoietin receptor ,Cancer Research ,medicine.drug_class ,business.industry ,Chronic lymphocytic leukemia ,Eltrombopag ,Salvage therapy ,hemic and immune systems ,Hematology ,medicine.disease ,Leukemia ,chemistry.chemical_compound ,Oncology ,chemistry ,immune system diseases ,hemic and lymphatic diseases ,Immunology ,medicine ,Neoplasm ,business ,Receptor ,reproductive and urinary physiology ,circulatory and respiratory physiology - Abstract
Eltrombopag, a second-generation thrombopoietin receptor agonist, for chronic lymphocytic leukemia-associated ITP
- Published
- 2010
26. Failure is not fatal: long-term remission in refractory acute myeloid leukemia (AML) after graft failure of cord blood stem cells
- Author
-
William G. Wierda, N S Velev, Elizabeth J. Shpall, Farhad Ravandi, Jeffrey L. Jorgensen, J. E. Cortes, Jan A. Burger, E. Jabbour, Hagop M. Kantarjian, and Yago Nieto
- Subjects
Cancer Research ,medicine.medical_specialty ,Hematology ,Myeloid ,business.industry ,Myeloid leukemia ,Cord Blood Stem Cell Transplantation ,medicine.disease ,Gastroenterology ,Transplantation ,Leukemia ,medicine.anatomical_structure ,Oncology ,hemic and lymphatic diseases ,Internal medicine ,Cord blood ,Immunology ,Medicine ,Stem cell ,business ,neoplasms - Abstract
Failure is not fatal: long-term remission in refractory acute myeloid leukemia (AML) after graft failure of cord blood stem cells
- Published
- 2010
27. Immunotherapy for chronic lymphocytic leukemia in the era of BTK inhibitors
- Author
-
William G. Wierda, Mohamed A. Kharfan-Dabaja, and Laurence J.N. Cooper
- Subjects
Cancer Research ,Cell Transplantation ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Hematopoietic stem cell transplantation ,chemistry.chemical_compound ,hemic and lymphatic diseases ,medicine ,Agammaglobulinaemia Tyrosine Kinase ,Immune Tolerance ,Bruton's tyrosine kinase ,Humans ,Lenalidomide ,Protein Kinase Inhibitors ,biology ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Immunotherapy ,Protein-Tyrosine Kinases ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chimeric antigen receptor ,Thalidomide ,Leukemia ,Oncology ,chemistry ,Ibrutinib ,Immunology ,biology.protein ,Cancer research ,business ,Tyrosine kinase - Abstract
Understanding the pathogenesis of CLL has uncovered a plethora of novel targets for human application of monoclonal antibodies, engineered T cells, or inhibitors of signal transduction pathways. The B-cell receptor signaling pathway is being actively explored as a therapeutic target in CLL. Ibrutinib, an inhibitor of Bruton's tyrosine kinase is showing impressive responses in heavily pre-treated high-risk CLL, whether alone or in combination with MoAbs or chemotherapy. Other key components of the BCR pathway, namely PI3K-δ, are also being targeted with novel therapies with promising results as well. Future trials would likely evaluate ibrutinib in the front-line setting. Moreover, improvements in allogeneic HCT mostly by continuing to reduce associated toxicity as well as incorporating cellular therapies such as autologous CLL tumor vaccines, among others, will continue to expand. This is also the case for the next generation of chimeric antigen receptor therapy for CLL once genetically modified T cells are available at broad scale and with improved efficacy. As our ability to further refine and integrate these therapies continues to improve, and we gain further knowledge from gene sequencing, we anticipate that treatment algorithms will continue to be revised to a more personalized approach to treat this disease with improved efficacy and devoid of unnecessary toxicity.
- Published
- 2013
28. A prognostic score for patients with lower risk myelodysplastic syndrome
- Author
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Hagop M. Kantarjian, Jorge E. Cortes, William G. Wierda, G. Garcia-Manero, Eli Estey, Xuelin Huang, J. Shan, Farhad Ravandi, Stephan Faderl, Jinyun Liu, Sherry Pierce, and G. Borthakur
- Subjects
Adult ,Male ,Risk ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Anemia ,Lower risk ,Severity of Illness Index ,Bone Marrow ,Internal medicine ,Epidemiology ,Severity of illness ,medicine ,Humans ,Survival analysis ,Aged ,Aged, 80 and over ,Chromosome Aberrations ,business.industry ,Platelet Count ,Myelodysplastic syndromes ,Age Factors ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Surgery ,Leukemia ,Oncology ,International Prognostic Scoring System ,Leukemia, Myeloid ,Myelodysplastic Syndromes ,Acute Disease ,Ferritins ,Disease Progression ,Female ,business ,beta 2-Microglobulin ,Follow-Up Studies - Abstract
Current prognostic models for myelodysplastic syndromes (MDS) do not allow the identification of patients with lower risk disease and poor prognosis that may benefit from early therapeutic intervention. We evaluated the characteristics of 856 patients with low or intermediate-1 disease by the International Prognostic Scoring System. Mean follow-up was 19.6 months (range 1-262). Of these patients, 87 (10%) transformed to acute myelogenous leukemia, and 429 (50%) had died. By multivariate analysis, characteristics associated with worse survival (P
- Published
- 2007
29. Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia
- Author
-
William G. Wierda, Michael J. Keating, Laura Z. Rassenti, Marina Motta, B J Shelvin, Thomas J. Kipps, and Susan Lerner
- Subjects
Adult ,Male ,Cancer Research ,Chronic lymphocytic leukemia ,T-Lymphocytes ,Lymphocyte Activation ,Interleukin 21 ,Immune system ,Antigens, CD ,Antigens, Neoplasm ,hemic and lymphatic diseases ,medicine ,Humans ,CTLA-4 Antigen ,IL-2 receptor ,Aged ,Cell Proliferation ,Aged, 80 and over ,business.industry ,Antibodies, Monoclonal ,Hematology ,T lymphocyte ,Middle Aged ,medicine.disease ,Flow Cytometry ,Antigens, Differentiation ,Leukemia, Lymphocytic, Chronic, B-Cell ,Coculture Techniques ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Leukemia ,Kinetics ,Oncology ,CTLA-4 ,Case-Control Studies ,Immunology ,Female ,business ,CD8 - Abstract
Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-naïve patients with CLL. CD4+ and CD8+ T cells from these patients demonstrated significantly increased sCD152 and cCD152 compared to normal donors. Furthermore, these patients had an increased proportion of the regulatory CD4(+)/CD25(+)/CD152+ subset that correlated with advanced Rai stage, unfavorable cytogenetics and low serum IgG and IgA levels. The expression of sCD152 by T cells also correlated with ZAP-70 expression by CLL B cells. The proportion of CD4(+)/CD25+ cells was also correlated with unmutated immunoglobulin heavy chain variable gene status. Blockade of CD152 with monoclonal antibody (mAb) in proliferation assays was associated with potent T-cell proliferation in response to autologous and allogeneic CD40-activated CLL B cells. In summary, T cells from patients with CLL may be primed for anergy by expressing increased amounts of CD152; anti-CD152 mAb may represent a therapeutic opportunity to enhance an immune response against autologous leukemia cells.
- Published
- 2005
30. Increased mitochondrial biogenesis in primary leukemia cells: the role of endogenous nitric oxide and impact on sensitivity to fludarabine
- Author
-
Steffan T. Nawrocki, Kenneth Dunner, David J. McConkey, M. J. Keating, Rui-Hua Xu, Jennifer S. Carew, Peng Huang, and William G. Wierda
- Subjects
Cancer Research ,Mitochondrial DNA ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Mitochondrion ,Biology ,Nitric Oxide ,Mitochondrial Proteins ,hemic and lymphatic diseases ,medicine ,Tumor Cells, Cultured ,Humans ,NRF1 ,DNA (Cytosine-5-)-Methyltransferases ,Lymphocytes ,Organelle Biogenesis ,Nuclear Respiratory Factor 1 ,Nuclear Proteins ,Hematology ,TFAM ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Mitochondria ,DNA-Binding Proteins ,Leukemia ,Oncology ,Mitochondrial biogenesis ,Drug Resistance, Neoplasm ,Immunology ,Cancer research ,Organelle biogenesis ,Vidarabine ,Transcription Factors - Abstract
B cell chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the Western hemisphere, yet many biological and molecular features of the disease remain undefined. CLL cells generate increased levels of radical species such as superoxide and nitric oxide (NO), which is associated with mitochondrial DNA mutations. Considering that NO levels can affect mitochondrial biogenesis, we hypothesized that the inherent nitrosative stress in CLL cells may lead to hyperactive mitochondrial biogenesis. Here we report that primary CLL cells contained significantly more mitochondria than normal lymphocytes and that their mitochondrial mass was significantly related to endogenous NO levels. Expression of the mitochondrial biogenesis factors nuclear respiratory factor-1 and mitochondrial transcription factor A was elevated in most CLL specimens examined and appeared to be related to cellular NO levels. Treatment of B cells with exogenous NO caused a substantial increase in mitochondrial mass. In vitro sensitivity of CLL cells to fludarabine was highly related to mitochondrial mass in that cells with greater mitochondrial mass were less sensitive to the drug. Taken together, our results suggest that NO is a key mediator of mitochondrial biogenesis in CLL and that modulation of mitochondrial biogenesis by NO may alter cellular sensitivity to fludarabine.
- Published
- 2004
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