27,881 results on '"Myeloid leukemia"'
Search Results
2. A Phase I/II Study of Gilteritinib and Momelotinib for Patients With Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia
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GlaxoSmithKline
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- 2024
3. Implantation of an Advanced Practice Nurse in the Complex Care Pathway of Patients With AML (LAMIPA)
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- 2024
4. Anti-Leukemia Immune Responses After Irradiation of Extramedullary Tumors
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- 2024
5. Interferon-α for TP53 Myeloid Malignancy Post Allo-HSCT
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Xiao-Jun Huang, Professor
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- 2024
6. Integrated Actionable Aging Assessment for Cancer Patients Pilot
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National Cancer Institute (NCI)
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- 2024
7. FT538 in Combination With Daratumumab in AML Acute Myeloid Leukemia
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- 2024
8. Reduced-Intensity Conditioning for the Prevention of Treatment-Related Mortality in Patients Who Undergo a Hematopoietic Stem Cell Transplant
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- 2024
9. Deciphering genetic and nongenetic factors underlying tumour dormancy: insights from multiomics analysis of two syngeneic MRD models of melanoma and leukemia.
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Laguillaumie, Marie-Océane, Titah, Sofia, Guillemette, Aurélie, Neve, Bernadette, Leprêtre, Frederic, Ségard, Pascaline, Shaik, Faruk Azam, Collard, Dominique, Gerbedoen, Jean-Claude, Fléchon, Léa, Hasan Bou Issa, Lama, Vincent, Audrey, Figeac, Martin, Sebda, Shéhérazade, Villenet, Céline, Kluza, Jérôme, Laine, William, Fournier, Isabelle, Gimeno, Jean-Pascal, and Wisztorski, Maxence
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MYELOID leukemia ,GENE expression ,MULTIOMICS ,PROTEOMICS ,GENE ontology ,IMMUNOPRECIPITATION ,DORMANCY in plants - Abstract
Background: Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. Results: We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared "murine MRD genes" profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. Conclusions: Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Characteristics and complications of acute promyelocytic leukemia in children: an analysis of a national database.
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Barhen, Ariella, Martinez, Paul A., Sendi, Prithvi, and Totapally, Balagangadhar R.
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ACUTE promyelocytic leukemia , *ACUTE myeloid leukemia , *MYELOID leukemia , *ACUTE leukemia , *HOSPITAL care of children - Abstract
Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia (AML) that was previously one of the most fatal forms of acute leukemia. With advances in diagnosis and treatment, APL has become one of the most curable myeloid leukemias. The major reason for treatment failure in APL is early death after initiation of treatment. We performed a retrospective cross-sectional analysis of the Healthcare Cost and Utilization Project 2016 and 2019 Kids' Inpatient Database, with the diagnosis of APL or AML not in remission as defined by ICD-10-CM codes. We compared complications and outcomes associated with APL and AML (exclusive of APL) in hospitalized children in the U.S. and described yearly national incidence. The national incidence of APL was 2.2 cases per million children per year. Children with APL were more likely to have cardiopulmonary complications (OR 1.79; CI 1.20–2.67; p = 0.004), coagulation abnormalities or DIC (OR 7.75; CI 5.81–10.34; p < 0.001), pulmonary hemorrhage (OR 2.18; CI 1.49–3.17; p < 0.001), and intracranial hemorrhage (OR 10.82; CI 5.90–19.85; p < 0.001) and less likely to have infectious complications (OR 0.48; CI 0.34–0.67; p < 0.001) compared to children with AML. In-hospital mortality rates were similar in children with APL and AML (4.2% vs 2.6%; OR 1.62; CI 0.86–3.06; p = 0.13), while the median length of stay for children who died from APL was shorter compared to AML (2 (IQR: 1–7) versus 25 (IQR: 5–66) days; p < 0.05). Hemorrhagic complications occur more often, and infectious complications occur less often in hospitalized children with APL compared to AML. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Concurrent myelodysplastic malignancies and plasma cell neoplasms; a clinicopathological study with prognostic implications.
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Adekunle, Folashade, Ko, Kyungmin, Craig, Jeffrey, Courville, Elizabeth, Williams, Eli, Aguilera, Nadine, and Obiorah, Ifeyinwa E.
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PLASMA cell diseases , *MYELOPROLIFERATIVE neoplasms , *PROGNOSIS , *PLASMA cells , *MYELOID leukemia - Abstract
AbstractPlasma cell neoplasms (PCN) have infrequently been reported in patients with myelodysplastic syndrome (MDS) and even more rarely in those with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). We report the clinicopathologic features of 26 patients with bone marrow myelodysplasia accompanied by PCN, including 21 patients with MDS and 5 with MDS/MPN. The clinicopathologic features of the MDS/MPN-PCN were compared to those of the MDS-PCN group and 68 cases of MDS/MPN without PCN, respectively. The MDS/MPN-PCN group was notable for increased reticulin fibrosis > grade 1 when compared to both the MDS/MPN (
p = 0.007) and MDS-PCN (p = 0.02) groups. MDS/MPN-PCN was associated with worse overall survival when compared with MDS-PCN (p = 0.03) and but not with MDS/MPN. Notably, hemoglobin level <8 g/dl (p = 0.008), andIDH2 somatic mutation (p = 0.003) were independent predictors of poor overall survival in all patients with MDS/MPN. Analysis of larger cohorts is required to confirm these associations and provide an insight into the pathogenesis. [ABSTRACT FROM AUTHOR]- Published
- 2024
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12. Myeloid sarcoma of the breast with synchronous early T‐cell precursor acute lymphoblastic leukemia: A rare presentation.
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Hajra, Subhajit, Ur, Kavya, Qamer, Zahed Ali, Kumar, Karthik, Balasubramanian, Priyavadhana, Dhingra, Gaurav, Singh, Neha, and Chowdhury, Nilotpal
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MYELOID sarcoma , *LYMPHOBLASTIC leukemia , *MYELOID leukemia , *ACUTE myeloid leukemia , *MYELODYSPLASTIC syndromes , *CHRONIC leukemia - Abstract
This article presents a case study of a 24-year-old female patient who was initially diagnosed with breast cancer but later developed a rare form of acute lymphoblastic leukemia called early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). The article suggests a possible connection between breast cancer and ETP-ALL, possibly involving a common progenitor. The patient's treatment was difficult due to the rarity and poor prognosis of ETP-ALL. The article concludes by emphasizing the need for further research to better understand the development and relationship of ETP-ALL to other types of leukemia. [Extracted from the article]
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- 2024
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13. Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.
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Che, Noelia, Cantilena, Sandra, Looi-Somoye, Remi, Sundar, Danesh, Fung, Kent, de Boer, Jasper, and Williams, Owen
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ACUTE promyelocytic leukemia , *ACUTE myeloid leukemia , *LYMPHOBLASTIC leukemia , *ACUTE leukemia , *MYELOID leukemia , *ARSENIC trioxide , *TRETINOIN - Abstract
Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Breaking Boundaries: Immunotherapy for Myeloid Malignancies.
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Gavrilova, Tatyana, Schulz, Eduard, and Mina, Alain
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MYELODYSPLASTIC syndromes treatment , *T cells , *KILLER cells , *IMMUNOTHERAPY , *CELLULAR therapy , *CANCER vaccines , *MONOCLONAL antibodies , *IMMUNE checkpoint inhibitors , *MYELOID leukemia - Abstract
Simple Summary: Patients with myeloid malignancies (blood cancers such as leukemia and myelodysplastic syndromes) that have returned or worsened despite chemotherapy or a stem cell transplant face limited treatment choices. Immunotherapy holds promise in deploying the body's own immune system to target and destroy cancer cells that are otherwise evading immune detection. This review article summarizes the most up to date information on immunotherapy options for patients with myeloid malignancies as well as discusses the challenges faced in this evolving field. Immunotherapy has revolutionized the treatment of myeloid oncologic diseases, particularly for patients resistant to chemotherapy or ineligible for allogeneic stem cell transplantation due to age or fitness constraints. As our understanding of the immunopathogenesis of myeloid malignancies expands, so too do the treatment options available to patients. Immunotherapy in myeloid malignancies, however, faces numerous challenges due to the dynamic nature of the disease, immune dysregulation, and the development of immune evasion mechanisms. This review outlines the progress made in the field of immunotherapy for myeloid malignancies, addresses its challenges, and provides insights into future directions in the field. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Enhancing Selectivity and Inhibitory Effects of Chemotherapy Drugs Against Myelogenous Leukemia Cells with Lippia alba Essential Oil Enriched in Citral.
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Quintero-García, Wendy Lorena, Espinel-Mesa, Denerieth Ximena, Moreno, Erika Marcela, Stashenko, Elena, Mesa-Arango, Ana Cecilia, and García, Liliana Torcoroma
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ACUTE myeloid leukemia , *MYELOID leukemia , *APOPTOSIS , *ESSENTIAL oils , *CELL death - Abstract
Acute myelogenous leukemia (AML) is one of the most lethal cancers, lacking a definitive curative therapy due to essential constraints related to the toxicity and efficacy of conventional treatments. This study explores the co-adjuvant potential of Lippia alba essential oils (EO) for enhancing the effectiveness and selectivity of two chemotherapy agents (cytarabine and clofarabine) against AML cells. EO derived from L. alba citral chemotype were produced using optimized and standardized environmental and extraction protocols. Rational fractionation techniques were employed to yield bioactive terpene-enriched fractions, guided by relative chemical composition and cytotoxic analysis. Pharmacological interactions were established between these fractions and cytarabine and clofarabine. The study comprehensively evaluated the cytotoxic, genotoxic, oxidative stress, and cell death phenotypes induced by therapies across AML (DA-3ER/GM/EVI1+) cells. The fraction rich in citral (F2) exhibited synergistic pharmacological interactions with the studied chemotherapies, intensifying their selective cytotoxic, genotoxic, and pro-oxidant effects. This shift favored transitioning from necrosis to a programmed cell death phenotype (apoptotic). The F2-clofarabine combination demonstrated remarkable synergistic anti-leukemic performance while preserving cell integrity in healthy cells. The observed selective antiproliferative effects may be attributed to the potential dual prooxidant/antioxidant behavior of citral in L. alba EO. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Prediction of leukemia peptides using convolutional neural network and protein compositions.
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Khawaja, Seher Ansar, Farooq, Muhammad Shoaib, Ishaq, Kashif, Alsubaie, Najah, Karamti, Hanen, Montero, Elizabeth Caro, Alvarado, Eduardo Silva, and Ashraf, Imran
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CONVOLUTIONAL neural networks , *RECURRENT neural networks , *LYMPHOCYTIC leukemia , *MYELOID leukemia , *NERVE tissue proteins - Abstract
Leukemia is a type of blood cell cancer that is in the bone marrow's blood-forming cells. Two types of Leukemia are acute and chronic; acute enhances fast and chronic growth gradually which are further classified into lymphocytic and myeloid leukemias. This work evaluates a unique deep convolutional neural network (CNN) classifier that improves identification precision by carefully examining concatenated peptide patterns. The study uses leukemia protein expression for experiments supporting two different techniques including independence and applied cross-validation. In addition to CNN, multilayer perceptron (MLP), gated recurrent unit (GRU), and recurrent neural network (RNN) are applied. The experimental results show that the CNN model surpasses competitors with its outstanding predictability in independent and cross-validation testing applied on different features extracted from protein expressions such as amino acid composition (AAC) with a group of AAC (GAAC), tripeptide composition (TPC) with a group of TPC (GTPC), and dipeptide composition (DPC) for calculating its accuracies with their receiver operating characteristic (ROC) curve. In independence testing, a feature expression of AAC and a group of GAAC are applied using MLP and CNN modules, and ROC curves are achieved with overall 100% accuracy for the detection of protein patterns. In cross-validation testing, a feature expression on a group of AAC and GAAC patterns achieved 98.33% accuracy which is the highest for the CNN module. Furthermore, ROC curves show a 0.965% extraordinary result for the GRU module. The findings show that the CNN model is excellent at figuring out leukemia illnesses from protein expressions with higher accuracy. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Clinical features and prognosis of patients with myeloid neoplasms harboring t(7;11)(p15;p15) translocation: a single-center retrospective study.
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Liu, Lin, Zhao, Shuqi, Wang, Lu, Xu, Huan, Chen, Zhimei, Tu, Jifang, Huang, Jiansong, Jin, Jie, and Tong, Hongyan
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SURVIVAL rate , *BLOOD cell count , *MYELOID leukemia , *LACTATE dehydrogenase , *ACUTE myeloid leukemia - Abstract
Background: For myeloid neoplasms with t(7;11)(p15;p15) translocation, the prognosis is quite dismal. Because these tumors are rare, most occurrences are reported as single cases. Clinical results and optimal treatment approaches remain elusive. This study endeavors to elucidate the clinical implications and prognosis of this cytogenetic aberration. Methods: This study retrospectively analyzed 23 cases of myeloid neoplasm with t(7;11)(p15;p15). Clinicopathological characteristics, genetic alterations, and outcomes were evaluated, and the Kaplan-Meier method was employed to construct survival curves. Results: Of these, nine cases were newly diagnosed acute myeloid leukemia (ND AML), seven presented with relapsed refractory AML (R/R AML), four had myelodysplastic syndrome (MDS), two had secondary AML, and one exhibited a mixed germinoma associated with MDS. Patients with t(7;11)(p15;p15) in AML were primarily younger females who preferred subtype M2. Interestingly, these patients had decreased hemoglobin and red blood cell counts, along with markedly elevated levels of lactic dehydrogenase and interleukin-6, and exhibited the expression of CD117. R/R AML patients exhibited a higher likelihood of additional chromosome abnormalities (ACAs) besides t(7;11). WT1 and FLT3-ITD were the most commonly found mutated genes, and 10 of those instances showed evidence of the NUP98::HOXA9 fusion gene. The composite complete remission rate was 66.7% (12/18), while the cumulative graft survival rate was 100% (4/4). However, the survival outcomes were dismal. Interestingly, the median overall survival for R/R AML patients was 4.0 months (95% CI: 1.7–6.4). Additionally, the type of AML diagnosis or the presence of ACAs or molecular prognostic stratification did not significantly influence clinical outcomes (p = 0.066, p = 0.585, p = 0.570, respectively). Conclusion: Myeloid leukemia with t(7;11) exhibits unique clinical features, cytogenetic properties, and molecular genetic characteristics. These survival outcomes were dismal. R/R AML patients have a limited lifespan. For myeloid patients with t(7;11), targeted therapy or transplantation may be an effective course of treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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18. RUNX1::ETO and CBFβ::MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core‐binding factor‐acute myeloid leukaemia.
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Wang, Siyang, Liu, Yabin, Zhao, Xujie, Wang, Xiaoling, Lou, Jiacheng, Jin, Peng, Zhang, Yi, Yu, Jinyi, and Wang, Kankan
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MYELOID leukemia , *AMINO acid metabolism , *GENE expression , *TREATMENT effectiveness , *CHIMERIC proteins - Abstract
Summary: Effectively targeting transcription factors in therapeutic interventions remains challenging, especially in core‐binding factor‐acute myeloid leukaemia (CBF‐AML) characterized by RUNX1::ETO and CBFβ::MYH11 fusions. However, recent studies have drawn attention towards aberrant amino acid metabolisms as actionable therapeutic targets. Here, by integrating the expression profile and genetic makeup in AML cohort, we found higher BCAT1 expression in CBF‐AML patients compared with other subtypes. Metabolic profiling revealed that high BCAT1 expression led to reprogrammed branch amino acid metabolism in CBF‐AML and was associated with sphingolipid pathway relating to the fitness of leukaemia cells, supported by transcriptomic profiling. Mechanistically, we demonstrated in cell lines and primary patient samples that BCAT1 was directly activated by RUNX1::ETO and CBFβ::MYH11 fusion proteins similarly in a RUNX1‐dependent manner through rewiring chromatin conformation at the BCAT1 gene locus. Furthermore, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis and myeloid differentiation of CBF‐AML cells in vitro, and alleviated leukaemia burden and prolonged survival in vivo. Importantly, pharmacological inhibition of BCAT1 using the specific inhibitor Gabapentin demonstrated therapeutic effects, as evidenced by delayed leukaemia progression and improved survival in vivo. In conclusion, our study uncovers BCAT1 as a genetic vulnerability and a promising targeted therapeutic opportunity for CBF‐AML. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Discernable machine learning methods for Raman micro‐spectroscopic stratification of mitoxantrone‐induced drug‐resistant cells in acute myeloid leukemia.
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Anjikar, Ajinkya, Iwasaki, Keita, Paneerselvam, Rajapandian, Hole, Arti, Chilakapati, Murali Krishna, Noothalapati, Hemanth, Dutt, Shilpee, and Yamamoto, Tatsuyuki
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FISHER discriminant analysis , *MYELOID leukemia , *ACUTE myeloid leukemia , *DRUG resistance in cancer cells , *PRINCIPAL components analysis - Abstract
Drug resistance plays a vital role in both cancer treatment and prognosis. Especially, early insights into such drug‐induced resistance in acute myeloid leukemia (AML) can help to improve treatment plans, reduce costs, and bring overall positive outcomes for patients. Raman spectroscopy provides precise biomolecular information and can provide all these necessities effectively. In this study, we employed machine learning (ML) discrimination of Raman micro‐spectroscopic data of myelocytic leukemia cell line HL‐60 from its drug‐resistant counterpart HL‐60/MX2. Principal component analysis (PCA), linear discriminant analysis (LDA), and logistic regression (LR) methods were evaluated for their ability to identify and discriminate drug resistance in AML cells. Our study demonstrates the power of ML to classify drug‐induced resistance in AML cells utilizing subtle variations in biomolecular information contained in molecular spectroscopic data by obtaining 94.11% and 97.05% classification accuracies by LDA and LR models, respectively. We also showed that the ML methods are discernable. Our findings depict the importance of automation and its optimal usage in cancer study and diagnosis. The results of our study are expected to take ML‐assisted Raman spectroscopy one step closer to making it a generalized tool in medical diagnosis in the future. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience †.
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Lucas, Bryony J., Connors, Jeremy S., Wang, Heping, Conneely, Shannon, Cuglievan, Branko, Garcia, Miriam B., and Rau, Rachel E.
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THERAPEUTIC use of antineoplastic agents , *THERAPEUTIC use of antimetabolites , *MYELOID leukemia genetics , *CYTOGENETICS , *NOONAN syndrome , *GERM cells , *AZACITIDINE , *MYELOPROLIFERATIVE neoplasms , *TREATMENT effectiveness , *RETROSPECTIVE studies , *CANCER chemotherapy , *MEDICAL records , *ACQUISITION of data , *MYELOID leukemia , *GENETIC mutation , *GENETICS , *ALLELES , *DISEASE complications , *CHILDREN - Abstract
Simple Summary: Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Given its rarity, management is not standardized and varies widely, ranging from observation to bone marrow transplant depending on genomic and clinical features. We describe the course of JMML or Noonan Syndrome-associated Myeloproliferative Disorder in 22 pediatric patients treated at three institutions to provide guidance for monitoring versus intervention, including transplant, supported by patient outcomes. We provide additional insight into the expected time to spontaneous resolution in those with germline PTPN11 mutations and treatment approaches for patients with germline CBL mutations where no standard exists. Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Computing cell state discriminates the aberrant hematopoiesis and activated microenvironment in Myelodysplastic syndrome (MDS) through a single cell genomic study.
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Guo, Xinyu, Jin, Wenyan, Wen, Yuchen, Wang, Zhiqin, Ren, Xiaotong, Liu, Zhaoyun, Fu, Rong, Cai, Zhigang, and Li, Lijuan
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MYELODYSPLASTIC syndromes , *HEMATOPOIESIS , *BONE marrow cells , *HEMATOPOIETIC stem cells , *MYELOID leukemia - Abstract
Background: Myelodysplastic syndrome (MDS) is a complicated hematopoietic malignancy characterized by bone marrow (BM) dysplasia with symptoms like anemia, neutropenia, or thrombocytopenia. MDS exhibits considerable heterogeneity in prognosis, with approximately 30% of patients progressing to acute myeloid leukemia (AML). Single cell RNA-sequencing (scRNA-seq) is a new and powerful technique to profile disease landscapes. However, the current available scRNA-seq datasets for MDS are only focused on CD34+ hematopoietic progenitor cells. We argue that using entire BM cell for MDS studies probably will be more informative for understanding the pathophysiology of MDS. Methods: Five MDS patients and four healthy donors were enrolled in the study. Unsorted cells from BM aspiration were collected for scRNA-seq analysis to profile overall alteration in hematopoiesis. Results: Standard scRNA-seq analysis of unsorted BM cells successfully profiles deficient hematopoiesis in all five MDS patients, with three classified as high-risk and two as low-risk. While no significant increase in mutation burden was observed, high-risk MDS patients exhibited T-cell activation and abnormal myelogenesis at the stages between hematopoietic stem and progenitor cells (HSPC) and granulocyte–macrophage progenitors (GMP). Transcriptional factor analysis on the aberrant myelogenesis suggests that the epigenetic regulator chromatin structural protein-encoding gene HMGA1 is highly activated in the high-risk MDS group and moderately activated in the low-risk MDS group. Perturbation of HMGA1 by CellOracle simulated deficient hematopoiesis in mouse Lineage-negative (Lin-) BM cells. Projecting MDS and AML cells on a BM cell reference by our newly developed MarcoPolo pipeline intuitively visualizes a connection for myeloid leukemia development and abnormalities of hematopoietic hierarchy, indicating that it is technically feasible to integrate all diseased bone marrow cells on a common reference map even when the size of the cohort reaches to 1,000 patients or more. Conclusion: Through scRNA-seq analysis on unsorted cells from BM aspiration samples of MDS patients, this study systematically profiled the development abnormalities in hematopoiesis, heterogeneity of risk, and T-cell microenvironment at the single cell level. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Functional characterization of native Piezo1 as calcium and magnesium influx pathway in human myeloid leukemia cells.
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Vasileva, Valeria Y., Lysikova, Daria V., Sudarikova, Anastasia V., Khairullina, Zuleikha M., Kirillova, Polina I., Morachevskaya, Elena A., and Chubinskiy‐Nadezhdin, Vladislav I.
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MYELOID leukemia , *CALCIUM channels , *MYELOID cells , *MAGNESIUM , *CALCIUM , *CHEMICAL agonists - Abstract
Piezo1 is a Ca2+‐permeable mechanically activated ion channel that is involved in various physiological processes and cellular responses to mechanical stimuli. The study of biophysical characteristics of Piezo1 is important for understanding the mechanisms of its function and regulation. Stretch activation, a routine approach that is applied to stimulate Piezo1 activity in the plasma membrane, has a number of significant limitations that complicate precise single‐channel analysis. Here, we aimed to determine pore properties of native Piezo1, specifically to examine permeation for physiologically relevant signaling divalent ions (calcium and magnesium) in human myeloid leukemia K562 cells using Piezo1‐specific chemical agonist, Yoda1. Using a combination of low‐noise single‐current patch‐clamp recordings of Piezo1 activity in response to Yoda1, we have determined single‐channel characteristics of native Piezo1 under various ionic conditions. Whole‐cell assay allowed us to directly measure Piezo1 single currents carried by Ca2+ or Mg2+ ions in the absence of other permeable cations in the extracellular solutions; unitary conductance values estimated at various concentrations of Mg2+ revealed strong saturation effect. Patch clamp data complemented with fluorescent imaging clearly evidenced Ca2+ and Mg2+ entry via native Piezo1 channel in human leukemia K562 cells. Mg2+ influx via Piezo1 was detected under quasi‐physiological conditions, thus showing that Piezo1 channels could potentially provide the physiological relevant pathway for Mg2+ ion transport and contribute to the regulation of Mg2+‐dependent intracellular signaling. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia.
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Auberger, Patrick, Favreau, Cécile, Savy, Coline, Jacquel, Arnaud, and Robert, Guillaume
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Phospholipid Hydroperoxide Gluthatione Peroxidase also called Glutathione Peroxidase 4 is one of the 25 described human selenoproteins. It plays an essential role in eliminating toxic lipid hydroxy peroxides, thus inhibiting ferroptosis and favoring cell survival. GPX4 is differentially expressed according to myeloid differentiation stage, exhibiting lower expression in hematopoietic stem cells and polymorphonuclear leucocytes, while harboring higher level of expression in common myeloid progenitors and monocytes. In addition, GPX4 is highly expressed in most of acute myeloid leukemia (AML) subtypes compared to normal hematopoietic stem cells. High GPX4 expression is consistently correlated to poor prognosis in patients suffering AML. However, the role of GPX4 in the development of the myeloid lineage and in the initiation and progression of myeloid leukemia remains poorly explored. Given its essential role in the detoxification of lipid hydroperoxides, and its overexpression in most of myeloid malignancies, GPX4 inhibition has emerged as a promising therapeutic strategy to specifically trigger ferroptosis and eradicate myeloid leukemia cells. In this review, we describe the most recent advances concerning the role of GPX4 and, more generally ferroptosis in the myeloid lineage and in the emergence of AML. We also discuss the therapeutic interest and limitations of GPX4 inhibition alone or in combination with other drugs as innovative therapies to treat AML patients. [ABSTRACT FROM AUTHOR]
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- 2024
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24. miR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia.
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Poggio, Pietro, Rocca, Stefania, Fusella, Federica, Ferretti, Roberta, Ala, Ugo, D'Anna, Flora, Giugliano, Emilia, Panuzzo, Cristina, Fontana, Diletta, Palumbo, Valeria, Carrà, Giovanna, Taverna, Daniela, Gambacorti-Passerini, Carlo, Saglio, Giuseppe, Fava, Carmen, Piazza, Rocco, Morotti, Alessandro, Orso, Francesca, and Brancaccio, Mara
- Subjects
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CHRONIC myeloid leukemia , *HEAT shock proteins , *MYELOID leukemia , *GENE expression , *BONE marrow - Abstract
Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients' bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients. [ABSTRACT FROM AUTHOR]
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- 2024
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25. A Second Wind for Inorganic APIs: Leishmanicidal and Antileukemic Activity of Hydrated Bismuth Oxide Nanoparticles.
- Author
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Grafov, Andriy, da Silva Chagas, Ana Flávia, de Freitas Gomes, Alice, Ouedrhiri, Wessal, Cerruti, Pierfrancesco, Del Barone, Maria Cristina, de Souza Mota, Breno, de Castro Alves, Carlos Eduardo, Brasil, Anny Maíza Vargas, Pereira, Antonia Maria Ramos Franco, and Soares Pontes, Gemilson
- Subjects
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CUTANEOUS leishmaniasis , *PERITONEAL macrophages , *CYTOTOXINS , *MYELOID leukemia , *BISMUTH trioxide , *LEISHMANIA - Abstract
American cutaneous leishmaniasis is a disease caused by protozoa of the genus Leishmania. Currently, meglumine antimoniate is the first-choice treatment for the disease. The limited efficacy and high toxicity of the drug results in the necessity to search for new active principles. Nanotechnology is gaining importance in the field, since it can provide better efficacy and lower toxicity of the drugs. The present study aimed to synthesize, characterize, and evaluate the in vitro leishmanicidal and antileukemic activity of bismuth nanoparticles (BiNPs). Promastigotes and amastigotes of L. (V.) guyanensis and L. (L.) amazonensis were exposed to BiNPs. The efficacy of the nanoparticles was determined by measurement of the parasite viability and the percentage of infected cells, while the cytotoxicity was characterized by the colorimetry. BiNPs did not induce cytotoxicity in murine peritoneal macrophages and showed better efficacy in inhibiting promastigotes (IC50 < 0.46 nM) and amastigotes of L. (L.) amazonensis. This is the first report on the leishmanicidal activity of Bi-based materials against L. (V.) guayanensis. BiNPs demonstrated significant cytotoxic activity against K562 and HL60 cells at all evaluated concentrations. While the nanoparticles also showed some cytotoxicity towards non-cancerous Vero cells, the effect was much lower compared to that on cancer cells. Treatment with BiNPs also had a significant effect on inhibiting and reducing colony formation in HL60 cells. These results indicate that bismuth nanoparticles have the potential for an inhibitory effect on the clonal expansion of cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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26. Acute myeloid leukemia (AML) with chromosome 3 inversion: biology, management, and clinical outcome.
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Alhajahjeh, Abdulrahman, Bewersdorf, Jan Philipp, Bystrom, Rebecca P., Zeidan, Amer M., Shimony, Shai, and Stahl, Maximilian
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CHROMOSOME inversions , *ACUTE myeloid leukemia , *TREATMENT effectiveness , *MYELOID leukemia , *STEM cell transplantation - Abstract
AbstractAcute myeloid leukemia (AML) is a complex hematological malignancy characterized by diverse genetic alterations, each with distinct clinical implications. Chromosome 3 inversion (inv(3)) is a rare genetic anomaly found in approximately 1.4–1.6% of AML cases, which profoundly affects prognosis. This review explores the pathophysiology of inv(3) AML, focusing on fusion genes like
GATA2::EVI1 orGATA2::MECOM . These genetic rearrangements disrupt critical cellular processes and lead to leukemia development. Current treatment modalities, including intensive chemotherapy (IC), hypomethylating agents (HMAs) combined with venetoclax, and allogeneic stem cell transplantation are discussed, highlighting outcomes achieved and their limitations. The review also addresses subgroups of inv(3) AML, describing additional mutations and their impact on treatment response. The poor prognosis associated with inv(3) AML underscores the urgent need to develop more potent therapies for this AML subtype. This comprehensive overview aims to contribute to a deeper understanding of inv(3) AML and guide future research and treatment strategies. [ABSTRACT FROM AUTHOR]- Published
- 2024
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27. Cutaneous Vasculitis as the Initial Presentation of Juvenile Myelomonocytic Leukemia.
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Estrella, Jewel, George, Simi, Hariri, Dana, Zaccarini, Daniel J., and Sura, Anjali
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SKIN disease diagnosis , *BIOPSY , *BLOOD testing , *COMPUTED tomography , *ULTRASONIC imaging , *SKIN , *FLUORESCENCE in situ hybridization , *MAGNETIC resonance angiography , *MYELOID leukemia , *GENETIC mutation ,VASCULAR disease diagnosis - Abstract
The article focuses on cutaneous vasculitis as an initial sign of juvenile myelomonocytic leukemia (JMML), emphasizing the importance of considering leukemia in patients presenting with vasculitis. Topics include the triad of leukocytosis, anemia, and thrombocytopenia as indicative of JMML, along with the significance of bone marrow biopsy in confirming the diagnosis.
- Published
- 2024
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28. 4‐Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders.
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Li, Ting, Li, Jia‐Wen, Qin, Ying‐Hui, Liu, Riu, Xu, Xiao‐Na, Li, Xiao, Li, Li‐Min, Feng, Bin, Yang, Li, and Yang, Chun‐Sheng
- Subjects
- *
NEUROMYELITIS optica , *MONONUCLEAR leukocytes , *NLRP3 protein , *MACROPHAGE inflammatory proteins , *CENTRAL nervous system diseases , *MYELOID leukemia - Abstract
Objective: Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene‐1 (IRG1) and the IRG1–itaconic acid–NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4‐octyl itaconate (4‐OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute‐onset NMOSD and to investigate the inhibitory effects of 4‐OI on NLRP3 inflammasome activation via the IRG1–itaconic acid–NLRP3 pathway in monocytes and macrophages by using in vitro models. Methods: Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3‐related inflammatory factors. Subsequently, the effects of 4‐OI on the IRG1–itaconic acid–NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP‐1 cells) via in vitro experiments. Results: Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4‐OI inhibited the activation of the IRG1–itaconic acid–NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. Interpretation: 4‐OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD‐derived PBMCs and in a human macrophage model. Thus, 4‐OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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29. Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3β Signaling Pathway.
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Jiang, Yu-xia, Zhao, Yan-na, Yu, Xiao-ling, and Yin, Li-ming
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BIOLOGICAL models ,PROTEIN kinases ,CARRIER proteins ,APOPTOSIS ,CELLULAR signal transduction ,CELL cycle ,DESCRIPTIVE statistics ,CELL lines ,MICE ,GENE expression ,IMMUNOHISTOCHEMISTRY ,GLYCOSIDES ,ANIMAL experimentation ,WESTERN immunoblotting ,CELL differentiation ,TRANSFERASES ,CELL survival ,SIGNAL peptides ,PEROXIDASE - Abstract
Objective: To investigate the role of ginsenoside Rd (GRd) in acute myeloid leukemia (AML) cell differentiation. Methods: AML cells were treated with GRd (25, 50, 100 and 200 µg/mL), retinoic acid (RA, 0.1g/L) and PD98059 (20 mg/mL) for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1 (GATA-1), purine rich Box-1 (PU.1), phosphorylated-extracellular signal-related kinase (p-ERK), ERK, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), GSK3β and signal transducer and activator of transcription 1 (STAT1) were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group (non-treated), GRd group [treated with 200 mg/(kg·d) GRd] and homoharringtonine (HTT) group [treated with 1 mg/(kg·d) HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining. Results: The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1 cell arrest (p<0.05). GRd treatment induced leukemia cell differentiation, showing increased expressions of peroxidase and specific proteins concerning erythrogenic or granulocytic differentiation (p<0.05). GRd treatment elicited upregulation of p-ERK, p-GSK-3β and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1 (P<0.05). After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis (P<0.05). WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor tissues (P<0.05 or P<0.01). Conclusion: GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3β signaling pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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30. Occupational exposure to benzene and mortality risk of lymphohaematopoietic cancers in the Swiss National Cohort.
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Ge, C., Egger, A. Spoerri M., Rothman, N., Lan, Q., Huss, A., and Vermeulen, R.
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OCCUPATIONAL exposure ,BENZENE ,DISEASE risk factors ,DIFFUSE large B-cell lymphomas - Published
- 2024
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31. Emerging role of glutathione peroxidase 4 in myeloid cell lineage development and acute myeloid leukemia
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Patrick Auberger, Cécile Favreau, Coline Savy, Arnaud Jacquel, and Guillaume Robert
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GPX4 ,Ferroptosis ,Myeloid differentiation ,Myeloid leukemia ,AML ,Small molecule inhibitors ,Cytology ,QH573-671 - Abstract
Abstract Phospholipid Hydroperoxide Gluthatione Peroxidase also called Glutathione Peroxidase 4 is one of the 25 described human selenoproteins. It plays an essential role in eliminating toxic lipid hydroxy peroxides, thus inhibiting ferroptosis and favoring cell survival. GPX4 is differentially expressed according to myeloid differentiation stage, exhibiting lower expression in hematopoietic stem cells and polymorphonuclear leucocytes, while harboring higher level of expression in common myeloid progenitors and monocytes. In addition, GPX4 is highly expressed in most of acute myeloid leukemia (AML) subtypes compared to normal hematopoietic stem cells. High GPX4 expression is consistently correlated to poor prognosis in patients suffering AML. However, the role of GPX4 in the development of the myeloid lineage and in the initiation and progression of myeloid leukemia remains poorly explored. Given its essential role in the detoxification of lipid hydroperoxides, and its overexpression in most of myeloid malignancies, GPX4 inhibition has emerged as a promising therapeutic strategy to specifically trigger ferroptosis and eradicate myeloid leukemia cells. In this review, we describe the most recent advances concerning the role of GPX4 and, more generally ferroptosis in the myeloid lineage and in the emergence of AML. We also discuss the therapeutic interest and limitations of GPX4 inhibition alone or in combination with other drugs as innovative therapies to treat AML patients.
- Published
- 2024
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32. Occupational exposure to benzene and mortality risk of lymphohaematopoietic cancers in the Swiss National Cohort
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Calvin Ge, Adrian Spoerri, Matthias Egger, Nathaniel Rothman, Qing Lan, Anke Huss, Roel Vermeulen, and The Swiss National Cohort
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occupational exposure ,benzene ,cancer ,lymphoma ,mortality risk ,lymphohaematopoietic cancer ,swiss national cohort ,myeloid leukemia ,Public aspects of medicine ,RA1-1270 - Abstract
OBJECTIVES: Previous studies established a causal relationship between occupational benzene exposure and acute myeloid leukemia (AML). However, mixed results have been reported for associations between benzene exposure and other myeloid and lymphoid malignancies. Our work examined whether occupational benzene exposure is associated with increased mortality from overall lymphohaematopoietic (LH) cancer and major subtypes. METHODS: Mortality records were linked to a Swiss census-based cohort from two national censuses in 1990 and 2000. Cases were defined as having any LH cancers registered in death certificates. We assessed occupational exposure by applying a quantitative benzene job-exposure matrix (BEN-JEM) to census-reported occupations. Exposure was calculated as the products of exposure proportions and levels (P × L). Cox proportional hazards models were used to calculate LH cancer death hazard ratios (HR) and 95% confidence intervals (CI) associated with benzene exposure, continuously and in ordinal categories. RESULTS: Our study included approximately 2.97 million persons and 13 415 LH cancer cases, including 3055 cases with benzene exposure. We observed increased mortality risks per unit (P × L) increase in continuous benzene exposure for AML (HR 1.03, 95% CI 1.00–1.06) and diffuse large B-cell lymphoma (HR 1.09, 95% CI 1.04–1.14). When exposure was assessed categorically, increasing trends in risks were observed with increasing benzene exposure for AML (P=0.04), diffuse large B-cell lymphoma (P=0.02), and follicular lymphoma (P=0.05). CONCLUSION: In a national cohort from Switzerland, we found that occupational exposure to benzene is associated with elevated mortality risks for AML, diffuse large B-cell lymphoma, and possibly follicular lymphoma.
- Published
- 2024
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33. IFN-γ to Treat Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) That Has Relapsed After Allogeneic Hematopoietic Stem Cell Transplantation
- Author
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Horizon Pharma USA, Inc. and Sawa Ito, MD, Assistant Professor
- Published
- 2023
34. Study of HQP1351 in Subjects With Refractory CML and Ph+ ALL
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- 2023
35. Therapeutic Use of Intravenous Vitamin C in Allogeneic Stem Cell Transplant Recipients
- Published
- 2023
36. Low‐dose decitabine plus venetoclax as post‐transplant maintenance for high‐risk myeloid malignancies
- Author
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Katherine Parks, Kendall Diebold, Donna Salzman, Antonio Di Stasi, Zaid Al‐Kadhimi, Manuel Espinoza‐Gutarra, Ravi Bhatia, and Omer Jamy
- Subjects
decitabine ,maintenance chemotherapy ,myeloid leukemia ,post‐transplant ,venetoclax ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Relapse remains a major cause of treatment failure following allogeneic stem cell transplantation (allo‐SCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We retrospectively investigated low‐dose decitabine and venetoclax (DEC/VEN) as post‐transplant maintenance in 26 older patients with AML and MDS. The cumulative incidence of day 100 gIII‐IV acute graft versus host disease (GVHD) and 1‐year moderate‐severe chronic GVHD was 5% and 26%, respectively. One patient relapsed 14 m after transplant. The 1‐year non‐relapse mortality and survival were 11% and 84%, respectively. DEC/VEN is a safe and potentially effective strategy to reduce the risk of post‐transplant relapse.
- Published
- 2024
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37. Study of chronic myeloid leukemia with T-cell under fractal-fractional order model
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Shah Kamal, Ahmad Shabir, Ullah Aman, and Abdeljawad Thabet
- Subjects
fractal-fractional operators ,myeloid leukemia ,model ,adams–basforth method ,Physics ,QC1-999 - Abstract
This research work is devoted to investigate myeloid leukemia mathematical model. We give some details about the existence of trivial and nontrivial equilibrium points and their stability. Also, local asymptotical stability of disease-free and endemic equilibrium points is discussed. Also, positivity of the solution has been discussed. Some sufficient results are achieved to study the local existence and uniqueness of solution to the considered model for Mittag–Leffler kernel using the Banach contraction theorem. Three numerical algorithms are derived in obtaining the numerical solution of suggested model under three different kernels using Adams–Basforth technique. Numerical results have been presented for different fractals and fractional orders to show the behavior of the proposed model.
- Published
- 2024
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- View/download PDF
38. Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.
- Author
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Khalaf, Ahmed, de Beauchamp, Lucie, Kalkman, Eric, Rattigan, Kevin, Himonas, Ekaterini, Jones, Joe, James, Daniel, Shokry, Engy Shokry Abd, Scott, Mary T., Dunn, Karen, Tardito, Saverio, Copland, Mhairi, Sumpton, David, Shanks, Emma, and Helgason, G. Vignir
- Subjects
CHRONIC myeloid leukemia ,DRUG repositioning ,DASATINIB ,MYELOID leukemia ,PROTEIN-tyrosine kinase inhibitors ,MITOCHONDRIA ,NILOTINIB - Abstract
In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)–approved voltage-gated Ca
2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+ CD38− ) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients. Editor's summary: Patients with chronic myeloid leukemia (CML) often relapse after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, because of persistent leukemic stem cells (LSCs). To target LSCs and overcome disease relapse, Khalaf et al. evaluated LSC reliance on mitochondrial respiration and oxidative phosphorylation (OXPHOS). They performed a screen in vitro to identify lomerizine, an FDA-approved voltage-gated calcium channel blocker as able to inhibit mitochondrial metabolism and sensitize CML LSCs to imatinib treatment. Combination in vivo extended survival of mouse models suggesting its potential for the treatment of patients with this disease. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]- Published
- 2024
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39. Prediction of miRNAs and diseases association based on sparse autoencoder and MLP.
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Si-Lin Sun, Bing-Wei Zhou, Sheng-Zheng Liu, Yu-Han Xiu, Bilal, Anas, and Hai-Xia Long
- Subjects
MULTILAYER perceptrons ,MICRORNA ,NON-coding RNA ,GENE expression ,LUPUS erythematosus ,MYELOID leukemia - Abstract
Introduction: MicroRNAs (miRNAs) are small and non-coding RNA molecules which have multiple important regulatory roles within cells. With the deepening research on miRNAs, more and more researches show that the abnormal expression of miRNAs is closely related to various diseases. The relationship between miRNAs and diseases is crucial for discovering the pathogenesis of diseases and exploring new treatment methods. Methods: Therefore, we propose a new sparse autoencoder and MLP method (SPALP) to predict the association between miRNAs and diseases. In this study, we adopt advanced deep learning technologies, including sparse autoencoder and multi-layer perceptron (MLP), to improve the accuracy of predicting miRNAdisease associations. Firstly, the SPALP model uses a sparse autoencoder to perform feature learning and extract the initial features of miRNAs and diseases separately, obtaining the latent features of miRNAs and diseases. Then, the latent features combine miRNAs functional similarity data with diseases semantic similarity data to construct comprehensive miRNAs-diseases datasets. Subsequently, the MLP model can predict the unknown association among miRNAs and diseases. Result: To verify the performance of our model, we set up several comparative experiments. The experimental results show that, compared with traditional methods and other deep learning prediction methods, our method has significantly improved the accuracy of predicting miRNAs-disease associations, with 94.61% accuracy and 0.9859 AUC value. Finally, we conducted case study of SPALP model. We predicted the top 30 miRNAs that might be related to Lupus Erythematosus, Ecute Myeloid Leukemia, Cardiovascular, Stroke, Diabetes Mellitus five elderly diseases and validated that 27, 29, 29, 30, and 30 of the top 30 are indeed associated. Discussion: The SPALP approach introduced in this study is adept at forecasting the links between miRNAs and diseases, addressing the complexities of analyzing extensive bioinformatics datasets and enriching the comprehension contribution to disease progression of miRNAs. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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40. Immunomodulatory and Anticancer Effects of Fridericia chica Extract-Loaded Nanocapsules in Myeloid Leukemia.
- Author
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de Freitas Gomes, Alice, Batalha, Adriane Dâmares de Souza Jorge, de Castro Alves, Carlos Eduardo, Galvão de Azevedo, Renata, Rodriguez Amado, Jesus Rafael, Pereira de Souza, Tatiane, Koolen, Hector Henrique Ferreira, da Silva, Felipe Moura Araújo, Chaves, Francisco Celio Maia, Florentino Neto, Serafim, Boechat, Antônio Luiz, and Soares Pontes, Gemilson
- Subjects
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MYELOID leukemia , *NANOCAPSULES , *ANTINEOPLASTIC agents , *BIOLOGICAL assay , *CELL survival , *CYTOTOXINS , *ANTIBODY-dependent cell cytotoxicity - Abstract
Nanocapsules provide selective delivery and increase the bioavailability of bioactive compounds. In this study, we examined the anticancer and immunomodulatory potential of Fridericia chica (crajiru) extract encapsulated in nanocapsules targeting myeloid leukemias. Nanocapsules containing crajiru (nanocapsules-CRJ) were prepared via interfacial polymer deposition and solvent displacement. Size and polydispersity were measured by dynamic light scattering. Biological assays were performed on leukemia cell lines HL60 and K562 and on non-cancerous Vero cells and human PBMC. The anticancer activity was evaluated using cytotoxicity and clonogenic assays, while the immunomodulatory activity was evaluated by measuring the levels of pro- and anti-inflammatory cytokines in PBMC supernatants treated with concentrations of nanocapsules-CRJ. Nanocapsules-CRJ exhibited significant cytotoxic activity against HL60 and K562 cells at concentrations ranging from 0.75 to 50 μg/mL, with the greatest reductions in cell viability observed at 50 μg/mL (p < 0.001 for HL60; p < 0.01 for K562), while not affecting non-cancerous Vero cells and human PBMCs. At concentrations of 25 μg/mL and 50 μg/mL, nanocapsules-CRJ reduced the formation of HL60 and K562 colonies by more than 90% (p < 0.0001). Additionally, at a concentration of 12 μg/mL, nanocapsules-CRJ induced the production of the cytokines IL-6 (p = 0.0002), IL-10 (p = 0.0005), IL-12 (p = 0.001), and TNF-α (p = 0.005), indicating their immunomodulatory potential. These findings suggest that nanocapsules-CRJ hold promise as a potential therapeutic agent with both cytotoxic and immunomodulatory properties. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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41. Overlapping Stromal Alterations in Myeloid and Lymphoid Neoplasms.
- Author
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Bogun, Lucienne, Koch, Annemarie, Scherer, Bo, Germing, Ulrich, Fenk, Roland, Maus, Uwe, Bormann, Felix, Köhrer, Karl, Petzsch, Patrick, Wachtmeister, Thorsten, Kobbe, Guido, Dietrich, Sascha, Haas, Rainer, Schroeder, Thomas, Geyh, Stefanie, and Jäger, Paul
- Subjects
- *
RNA analysis , *LYMPHOMA risk factors , *MYELODYSPLASTIC syndromes , *NON-Hodgkin's lymphoma , *BONE marrow , *RESEARCH funding , *MYELOPROLIFERATIVE neoplasms , *CELLULAR signal transduction , *DESCRIPTIVE statistics , *HEMATOPOIESIS , *GENE expression , *STROMAL cells , *MYELOID leukemia , *HEMATOPOIETIC stem cells , *LYMPHOBLASTIC leukemia , *CELL differentiation , *DISEASE progression , *SEQUENCE analysis ,BONE marrow cancer - Abstract
Simple Summary: Simple Summary: Myeloid and lymphoid malignant cells can become the dominant population in the bone marrow and thus inhibit healthy hematopoiesis. Patients suffer enormously as a result. In addition to the directly mediated inhibition of healthy hematopoietic stem and progenitor cells, indirect mechanisms via so-called mesenchymal stromal cells can also play a role. We are focusing our research on the latter and would like to identify functional and molecular overlapping mechanisms within the various myeloid and lymphoid neoplasms. In the future, it may be possible to block these mechanisms and thus prevent disease progression or improve healthy hematopoiesis. Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n = 44) and patients diagnosed with myeloproliferative neoplasia (n = 11), myelodysplastic syndromes (n = 16), or acute myeloid leukemia (n = 25) and B-Non-Hodgkin lymphoma (n = 9) with BM infiltration and acute lymphoblastic leukemia (n = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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42. In silico Evaluation of the Antileukemia Activities of Thymoquinone by Targeting FLT3-ITD and BCR-ABL Signaling in Myeloid leukemia.
- Author
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Al-Rawashde, Futoon Abedrabbu, Alqaraleh, Moath, Alhmoud, Jehad F., Al-Sanabra, Ola M., Saad, Hanan Kamel M., Odat, Nidal, Vishkaei, Mansoureh Nazari, and Nagi Al-Jamal, Hamid Ali
- Subjects
MYELOID leukemia ,PHOSPHATIDYLINOSITOL 3-kinases ,RAPAMYCIN ,DRUG resistance ,GENETIC mutation - Abstract
The FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) represents a distinct genetic mutation that characterizes acute myeloid leukaemia (AML). The breakpoint cluster region (BCR)-Abelson murine leukaemia (ABL) (BCR-ABL) is a key initiator of chronic myeloid leukaemia (CML) Hyperactivation of phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling is crucial in AML and CML pathogenesis. The recent development of tyrosine kinase inhibitors (TKIs) contributed to substantial improvements in leukaemia therapy. However, most leukaemia patients fail to completely recover and develop drug resistance after prolonged TKI therapy. Thymoquinone (TQ), a major ingredient of Nigella sativa seeds, has anti-tumour properties in a variety of cancers. However, the anti-leukemia effect of TQ was not extensively studied. Thus, the current research aims to identify TQ’s ability to bind on the active sites inFLT3-ITD, BCR-ABL, PI3K, Akt, and mTOR tyrosine kinases. The molecular docking of TQ toFLT3-ITD, BCR-ABL, PI3K, Akt, and mTOR was evaluated. Midostaurin; FLT3-ITD inhibitor, imatinib; BCR-ABL inhibitor, wortmannin; PI3K inhibitor, AZD5363; Akt inhibitor, and rapamycin; mTOR inhibitor were selected as positive controls. The findings revealed that TQ interacts with high affinities with the active site of PI3K(-7.02Kcal/mol), Akt(-6.4Kcal/mol), mTOR(-6.58Kcal/mol), FLT3- ITD(-6.35Kcal/mol), and BCR-ABL(-6.31Kcal/mol) and with low free binding energy to inhibit their enzymatic activities. In conclusion, TQ could potentially act as a TKI for FLT3- ITD, BCR-ABL, PI3K, Akt, and mTOR tyrosine kinases suggesting that TQ could act as a promising multi-targeted TKI for several tyrosine kinases for AML and CML treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
43. Tweaking the NRF2 signaling cascade in human myelogenous leukemia cells by artificial nano-organelles.
- Author
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Wolf, Konstantin M. P., Maffeis, Viviana, Schoenenberger, Cora-Ann, Zünd, Tamara, Bar-Peled, Liron, Palivan, Cornelia G., and Vogel, Viola
- Subjects
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MYELOID leukemia , *ARTIFICIAL cells , *NUCLEAR factor E2 related factor , *MONONUCLEAR leukocytes , *REACTIVE oxygen species - Abstract
NRF2 (nuclear factor erythroid-2-related factor 2) is a key regulator of genes involved in the cell's protective response to oxidative stress. Upon activation by disturbed redox homeostasis, NRF2 promotes the expression of metabolic enzymes to eliminate reactive oxygen species (ROS). Cell internalization of peroxisome-like artificial organelles that harbor redox-regulating enzymes was previously shown to reduce ROS-induced stress and thus cell death. However, if and to which extent ROS degradation by such nanocompartments interferes with redox signaling pathways is largely unknown. Here, we advance the design of H2O2-degrading artificial nano-organelles (AnOs) that exposed surface-attached cell penetrating peptides (CPP) for enhanced uptake and were equipped with a fluorescent moiety for rapid visualization within cells. To investigate how such AnOs integrate in cellular redox signaling, we engineered leukemic K562 cells that report on NRF2 activation by increased mCherry expression. Once internalized, ROS-metabolizing AnOs dampen intracellular NRF2 signaling upon oxidative injury by degrading H2O2. Moreover, intracellular AnOs conferred protection against ROS-induced cell death in conditions when endogenous ROS-protection mechanisms have been compromised by depletion of glutathione or knockdown of NRF2. We demonstrate CPP-facilitated AnO uptake and AnO-mediated protection against ROS insults also in the T lymphocyte population of primary peripheral blood mononuclear cells from healthy donors. Overall, our data suggest that intracellular AnOs alleviated cellular stress by the on-site reduction of ROS. [ABSTRACT FROM AUTHOR]
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- 2024
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44. The Functional Roles of the Src Homology 2 Domain-Containing Inositol 5-Phosphatases SHIP1 and SHIP2 in the Pathogenesis of Human Diseases.
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Müller, Spike Murphy and Jücker, Manfred
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TUMOR suppressor genes , *TUMOR suppressor proteins , *INOSITOL , *ALZHEIMER'S disease , *CARCINOGENESIS , *MYELOID leukemia , *PATHOGENESIS - Abstract
The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer's disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer's disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
45. Ring finger protein 138 inhibits transcription factor C/EBPα protein turnover leading to differentiation arrest in acute myeloid leukemia.
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Singh, Anil Kumar, Upadhyay, Vishal, Sethi, Arppita, Chowdhury, Sangita, Mishra, Shivkant, Verma, Shailendra Prasad, Bhatt, Madan Lal Brahma, and Trivedi, Arun Kumar
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TRANSCRIPTION factors , *ACUTE myeloid leukemia , *MONONUCLEAR leukocytes , *MYELOID leukemia , *CELL receptors , *MYELOID differentiation factor 88 , *UBIQUITINATION , *ESTROGEN receptors - Abstract
E3 ubiquitin ligase, ring finger protein 138 (RNF138) is involved in several biological processes; however, its role in myeloid differentiation or tumorigenesis remains unclear. RNAseq data from TNMplot showed that RNF138 mRNA levels are highly elevated in acute myeloid leukemia (AML) bone marrow samples as compared with bone marrow of normal volunteers. Here, we show that RNF138 serves as an E3 ligase for the tumor suppressor CCAAT/enhancer binding protein (C/EBPα) and promotes its degradation leading to myeloid differentiation arrest in AML. Wild-type RNF138 physically interacts with C/EBPα and promotes its ubiquitin-dependent proteasome degradation while a mutant RNF-138 deficient in ligase activity though interacts with C/EBPα, fails to down-regulate it. We show that RNF138 depletion enhances endogenous C/EBPα levels in peripheral blood mononuclear cells (PBMCs) isolated from healthy volunteers. Our data further shows that RNF138-mediated degradation of C/EBPα negatively affects its transactivation potential on its target genes. Furthermore, RNF138 overexpression inhibits all-transretinoic acid-induced differentiation of HL-60 cells whereas RNF138 RNAi enhances. In line with RNF138 inhibiting C/EBPα protein turnover, we also observed that RNF138 overexpression inhibited β-estradiol (E2)-induced C/EBPα driven granulocytic differentiation in C/EBPα inducible K562-p42C/EBPα-estrogen receptor cells. Furthermore, we also recapitulated these findings in PBMCs isolated from AML patients where depletion of RNF138 increased the expression of myeloid differentiation marker CD11b. These results suggest that RNF138 inhibits myeloid differentiation by targeting C/EBPα for proteasomal degradation and may provide a plausible mechanism for loss of C/EBPα expression often observed in myeloid leukemia. Also, targeting RNF138 may resolve differentiation arrest by restoring C/EBPα expression in AML. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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46. Herpesvirus Entry Mediator as an Immune Checkpoint Target and a Potential Prognostic Biomarker in Myeloid and Lymphoid Leukemia.
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Basingab, Fatemah S., Alzahrani, Reem A., Alrofaidi, Aisha A., Barefah, Ahmed S., Hammad, Rawan M., Alahdal, Hadil M., Alrahimi, Jehan S., Zaher, Kawther A., Algiraigri, Ali H., El-Daly, Mai M., Alkarim, Saleh A., and Aldahlawi, Alia M.
- Subjects
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T cells , *IMMUNE checkpoint proteins , *LYMPHOCYTIC leukemia , *MONONUCLEAR leukocytes , *MYELOID leukemia , *LYMPHOBLASTIC leukemia - Abstract
Herpesvirus entry mediator (HVEM) is a molecular switch that can modulate immune responses against cancer. The significance of HVEM as an immune checkpoint target and a potential prognostic biomarker in malignancies is still controversial. This study aims to determine whether HVEM is an immune checkpoint target with inhibitory effects on anti-tumor CD4+ T cell responses in vitro and whether HVEM gene expression is dysregulated in patients with acute lymphocytic leukemia (ALL). HVEM gene expression in tumor cell lines and peripheral blood mononuclear cells (PBMCs) from ALL patients and healthy controls was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Tumor cells were left untreated (control) or were treated with an HVEM blocker before co-culturing with CD4+ T cells in vitro in a carboxyfluorescein succinimidyl ester (CFSE)-dependent proliferation assay. HVEM expression was upregulated in the chronic myelogenous leukemia cell line (K562) (FC = 376.3, p = 0.086) compared with normal embryonic kidney cells (Hek293). CD4+ T cell proliferation was significantly increased in the HVEM blocker-treated K562 cells (p = 0.0033). Significant HVEM differences were detected in ALL PBMCs compared with the controls, and these were associated with newly diagnosed ALL (p = 0.0011) and relapsed/refractory (p = 0.0051) B cell ALL (p = 0.0039) patients. A significant differentiation between malignant ALL and the controls was observed in a receiver operating characteristic (ROC) curve analysis with AUC = 0.78 ± 0.092 (p = 0.014). These results indicate that HVEM is an inhibitory molecule that may serve as a target for immunotherapy and a potential ALL biomarker. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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47. Systematic and Therapeutic Applications to Understand the Mechanisms of Drug Resistance in Pediatric Acute Myeloid Leukemia through Network Pharmacology.
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RENPENG JIANG, WEIHONG LIU, YAN MA, and GUANGJUN WANG
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ACUTE myeloid leukemia , *DRUG resistance , *MYELOID leukemia , *CATECHIN , *PLANT polyphenols , *MYELOID cells , *PHARMACOLOGY , *GENE regulatory networks - Abstract
Studies have shown that natural flavone and flavonoids are molecules derived from the natural source and can selectively kill certain cancer cells. However, the exact process by which these bioactive substances affect acute myeloid leukemia is still unknown. To further understand about the medication resistance and find possible treatments for pediatric acute myeloid leukemia, we used network pharmacology methods. We specifically examined the pharmacological impacts of polyphenols, particularly kaempferol, catechin and quercetin on the treatment of acute myeloid leukemia. Using public databases including PubChem, Kyoto Encyclopedia of Genes and Genomes Mapper, Universal Protein Resource, DisGenet and cystoscope databases, we conducted a thorough search for the potential targets of polyphenols and acute myeloid leukemia. Consequently, we identified polyphenol target genes and acute myeloid leukemia disease targets. Among the 253 genes showed overlapping; however, some might be potential as polyphenol-based acute myeloid leukemia therapy targets. The specific method by which these bioactive substances exert their anti-acute myeloid leukemia effects has been elucidated through the use of protein-protein interaction network analysis, gene ontology analysis and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis. Further cytological examinations confirmed these results, illustrating the polyphenol's capacity to hinder the growth of acute myeloid leukemia cells through different pathways. Our study combines network pharmacology-based predictions with systematic review studies for polyphenolic-mediated therapy of acute myeloid leukemia. This provides new perspectives on therapeutic approaches to address drug resistance in pediatric acute myeloid leukemia. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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48. Antileukemic potential of methylated indolequinone MAC681 through immunogenic necroptosis and PARP1 degradation.
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Orlikova-Boyer, Barbora, Lorant, Anne, Gajulapalli, Sruthi Reddy, Cerella, Claudia, Schnekenburger, Michael, Lee, Jin-Young, Paik, Ji Yeon, Lee, Yejin, Siegel, David, Ross, David, Han, Byung Woo, Nguyen, Thi Kim Yen, Christov, Christo, Kang, Hyoung Jin, Dicato, Mario, and Diederich, Marc
- Subjects
CHRONIC myeloid leukemia ,MYELOID leukemia ,DNA repair ,PHAGOCYTIC function tests ,MYELOID cells ,MITOCHONDRIAL membranes ,PROTEIN-tyrosine kinase inhibitors ,LUCIFERASES ,POLY ADP ribose - Abstract
Background: Despite advancements in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), resistance and intolerance remain significant challenges. Leukemia stem cells (LSCs) and TKI-resistant cells rely on altered mitochondrial metabolism and oxidative phosphorylation. Targeting rewired energy metabolism and inducing non-apoptotic cell death, along with the release of damage-associated molecular patterns (DAMPs), can enhance therapeutic strategies and immunogenic therapies against CML and prevent the emergence of TKI-resistant cells and LSC persistence. Methods: Transcriptomic analysis was conducted using datasets of CML patients' stem cells and healthy cells. DNA damage was evaluated by fluorescent microscopy and flow cytometry. Cell death was assessed by trypan blue exclusion test, fluorescent microscopy, flow cytometry, colony formation assay, and in vivo Zebrafish xenografts. Energy metabolism was determined by measuring NAD
+ and NADH levels, ATP production rate by Seahorse analyzer, and intracellular ATP content. Mitochondrial fitness was estimated by measurements of mitochondrial membrane potential, ROS, and calcium accumulation by flow cytometry, and morphology was visualized by TEM. Bioinformatic analysis, real-time qPCR, western blotting, chemical reaction prediction, and molecular docking were utilized to identify the drug target. The immunogenic potential was assessed by high mobility group box (HMGB)1 ELISA assay, luciferase-based extracellular ATP assay, ectopic calreticulin expression by flow cytometry, and validated by phagocytosis assay, and in vivo vaccination assay using syngeneic C57BL/6 mice. Results: Transcriptomic analysis identified metabolic alterations and DNA repair deficiency signatures in CML patients. CML patients exhibited enrichment in immune system, DNA repair, and metabolic pathways. The gene signature associated with BRCA mutated tumors was enriched in CML datasets, suggesting a deficiency in double-strand break repair pathways. Additionally, poly(ADP-ribose) polymerase (PARP)1 was significantly upregulated in CML patients' stem cells compared to healthy counterparts. Consistent with the CML patient DNA repair signature, treatment with the methylated indolequinone MAC681 induced DNA damage, mitochondrial dysfunction, calcium homeostasis disruption, metabolic catastrophe, and necroptotic-like cell death. In parallel, MAC681 led to PARP1 degradation that was prevented by 3-aminobenzamide. MAC681-treated myeloid leukemia cells released DAMPs and demonstrated the potential to generate an immunogenic vaccine in C57BL/6 mice. MAC681 and asciminib exhibited synergistic effects in killing both imatinib-sensitive and -resistant CML, opening new therapeutic opportunities. Conclusions: Overall, increasing the tumor mutational burden by PARP1 degradation and mitochondrial deregulation makes CML suitable for immunotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
49. Acute Myelomonoblastic Leukemia (My1/De): A Preclinical Rat Model.
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ARATÓ, VIKTÓRIA, KÉPES, ZITA, SZABÓ, JUDIT P., FARKASINSZKY, GERGELY, SASS, TAMÁS, DÉNES, NOÉMI, KIS, ADRIENN, OPPOSITS, GÁBOR, JÓSZAI, ISTVÁN, KÁLMÁN, FERENC KRISZTIÁN, HAJDU, ISTVÁN, TRENCSÉNYI, GYÖRGY, and KERTÉSZ, ISTVÁN
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MYELOID leukemia ,LEUKEMIA diagnosis ,POSITRON emission tomography ,AUTORADIOGRAPHY ,LEUKEMIA treatment - Abstract
Background/Aim: Since acute myeloid leukemias still represent the most aggressive type of adult acute leukemias, the profound understanding of disease pathology is of paramount importance for diagnostic and therapeutic purposes. Hence, this study aimed to explore the real-time disease fate with the establishment of an experimental myelomonoblastic leukemia (My1/De) rat model using preclinical positron emission tomography (PET) and wholebody autoradiography. Materials and Methods: In vitro [18F]F-FDG uptake studies were performed to compare the tracer accumulation in the newly cultured My1/De tumor cell line (blasts) with that in healthy control and My1/De bone marrow suspensions. Post transplantation of My1/De cells under the left renal capsule of Long-Evans rats, primary My1/De tumorigenesis, and metastatic propagation were investigated using [18F]F-FDG PET imaging, whole-body autoradiography and phosphorimage analyses. To assess the organ uptake profile of the tumor-carrying animals we accomplished ex vivo biodistribution studies. Results: The tracer accumulation in the My1/De culture cells exceeded that of both the tumorous and the healthy bone marrow suspensions (p<0.01). Based on in vivo imaging, the subrenally transplanted My1/De cells resulted in the development of leukemia in the abdominal organs, and metastasized to the mesenterial and thoracic parathymic lymph nodes (PTLNs). The lymphatic spread of metastasis was further confirmed by the significantly higher %ID/g values of the metastatic PTLNs (4.25±0.28) compared to the control (0.94±0.34). Cytochemical staining of the peripheral blood, autopsy findings, and wright-Giemsa-stained postmortem histological sections proved the leukemic involvement of the assessed tissues/organs. Conclusion: The currently established My1/De model appears to be wellsuited for further leukemia-related therapeutic and diagnostic investigations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Acquired immune resistance is associated with interferon signature and modulation of KLF6/c‐MYB transcription factors in myeloid leukemia.
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Parveen, Mubaida, Karaosmanoglu, Beren, Sucularli, Ceren, Uner, Aysegul, Taskiran, Ekim Z., and Esendagli, Gunes
- Subjects
MYELOID leukemia ,TRANSCRIPTION factors ,INTERFERONS ,ACUTE myeloid leukemia ,BIOMARKERS - Abstract
Resistance to immunity is associated with the selection of cancer cells with superior capacities to survive inflammatory reactions. Here, we tailored an ex vivo immune selection model for acute myeloid leukemia (AML) and isolated the residual subpopulations as "immune‐experienced" AML (ieAML) cells. We confirmed that upon surviving the immune reactions, the malignant blasts frequently decelerated proliferation, displayed features of myeloid differentiation and activation, and lost immunogenicity. Transcriptomic analyses revealed a limited number of commonly altered pathways and differentially expressed genes in all ieAML cells derived from distinct parental cell lines. Molecular signatures predominantly associated with interferon and inflammatory cytokine signaling were enriched in the AML cells resisting the T‐cell‐mediated immune reactions. Moreover, the expression and nuclear localization of the transcription factors c‐MYB and KLF6 were noted as the putative markers for immune resistance and identified in subpopulations of AML blasts in the patients' bone marrow aspirates. The immune modulatory capacities of ieAML cells lasted for a restricted period when the immune selection pressure was omitted. In conclusion, myeloid leukemia cells harbor subpopulations that can adapt to the harsh conditions established by immune reactions, and a previous "immune experience" is marked with IFN signature and may pave the way for susceptibility to immune intervention therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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