Publications by authors named "Ambrine Sahal"
Protective immune responses require close interactions between conventional (Tconv) and regulatory T cells (Treg). The extracellular mediators and signaling events that regulate the crosstalk between these CD4 T cell subsets have been extensively characterized. However, how Tconv translate Treg-dependent suppressive signals at the chromatin level remains largely unknown.
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- The study investigates the role of autophagy induced by ruxolitinib in JAK2-driven myeloproliferative neoplasms (MPNs), highlighting its association with treatment resistance.
- Ruxolitinib activates protein phosphatase 2A (PP2A), leading to autophagy in JAK2 cells, and inhibiting either autophagy or PP2A enhances the drug's effectiveness by reducing cell proliferation and increasing their death.
- Using a strong autophagy inhibitor, Lys05, alongside ruxolitinib improved treatment outcomes in mice by reducing leukemia burden and extending survival, suggesting that targeting autophagy could make JAK2 MPN therapies more effective.
Unlabelled: Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival.
View Article and Find Full Text PDFUnlabelled: Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSC) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells.
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- The study explores the role of the transcription factor CCAAT-enhancer binding protein α (C/EBPα) in lipid metabolism and cellular homeostasis in acute myeloid leukemia (AML), particularly with mutations in FLT3.
- Researchers found that C/EBPα and FLT3 activation enhance lipid production and desaturation in AML cells, leading to increased vulnerability to oxidative stress.
- Inhibiting C/EBPα or FLT3 demonstrates potential for therapeutic strategies targeting lipid metabolism to promote ferroptotic cell death in FLT3-mutant AML, a type of leukemia affecting 30% of patients.
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- Recent advances in targeted therapies for acute myeloid leukemia (AML) have not significantly addressed many cases, especially those lacking actionable therapy targets.
- In a study of 127 AML cases, 40% showed alterations in RAS pathway genes, which correlated with worse outcomes and survival rates for patients.
- The combination of the MEK inhibitor trametinib and the anti-helminthic drug pyrvinium pamoate showed promising antileukemic effects in both laboratory tests and mouse models, suggesting a potential new treatment strategy for RAS+ AML.
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- Therapy resistance is a big issue in treating acute myeloid leukemia (AML), and researchers have created a 'MitoScore' to identify patients with high oxidative phosphorylation in their cells.
- AML cells that resist treatment with cytarabine (AraC) show reliance on certain mitochondrial proteins and respond well to a combination of venetoclax (VEN) and AraC, but not to VEN with azacytidine.
- Further research found that resistant AML cells adapt by altering their mitochondrial functions, and targeting these adaptations could improve treatment outcomes, suggesting a potential strategy to alternate between VEN therapies based on MitoScore levels to boost effectiveness.
Nonterminal blood sampling in laboratory mice is a very common procedure. With the goal of improving animal welfare, different sampling sites and methods have been compared but have not achieved a consensus. Moreover, most of these studies overlooked the quality of blood specimens collected.
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- AMPK is a key regulator of energy balance in cells, influencing growth and survival, and activation of AMPK has shown potential anti-cancer effects, particularly in acute myeloid leukemia (AML).
- The study reveals that the AMPK activator GSK621 triggers the unfolded protein response (UPR) in AML cells, causing changes in energy metabolism that promote cell death.
- Combining GSK621 with the Bcl-2 inhibitor venetoclax enhances the effectiveness of treatment, suggesting that AMPK activation could be a promising strategy for AML therapy through reshaping mitochondrial processes.
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- * IDH mutations found in preleukemic stem cells are stable at relapse, suggesting that targeting these cells could help achieve long-term remission in AML patients with IDH mutations.
- * Research indicates that the oncometabolite (R)-2-HG produced by IDH mutant enzymes activates vitamin D receptor pathways, enhancing the differentiation of AML cells when treated with ATRA and/or vitamin D, offering a new therapeutic strategy for these patients.
Oxidative metabolism is crucial for leukemic stem cell (LSC) function and drug resistance in acute myeloid leukemia (AML). Mitochondrial metabolism also affects the immune system and therefore the anti-tumor response. The modulation of oxidative phosphorylation (OxPHOS) has emerged as a promising approach to improve the therapy outcome for AML patients.
View Article and Find Full Text PDFMutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells.
View Article and Find Full Text PDFDrug tolerant/resistant leukemic stem cell (LSC) subpopulations may explain frequent relapses in acute myeloid leukemia (AML), suggesting that these relapse-initiating cells (RICs) persistent after chemotherapy represent bona fide targets to prevent drug resistance and relapse. We uncover that calcitonin receptor-like receptor (CALCRL) is expressed in RICs, and that the overexpression of CALCRL and/or of its ligand adrenomedullin (ADM), and not CGRP, correlates to adverse outcome in AML. CALCRL knockdown impairs leukemic growth, decreases LSC frequency, and sensitizes to cytarabine in patient-derived xenograft models.
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