Ena-DATASET-WEHI-30-03-2021-00:44:27:049-462 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001007307 | EGA |
REPOSITORIES: EGA
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Project description:The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML. Two samples were analyzed (untreated cells, cells treated with JQ1)
2014-01-01 | E-GEOD-51950 | biostudies-arrayexpress
Project description:Frontline use of the BCL2 inhibitor, venetoclax, for acute myeloid leukemia (AML) has resulted in broad improvements in patient outcome. A major remaining challenge is the development of venetoclax resistance, frequently driven by compensatory transcriptional programs that promote cell survival and differentiation. These changes reduce dependence on BCL2 in favor of alternative anti-apoptotic BCL2 family members such as MCL1 or BCL2L1 (BCL-XL). Using CRISPR-based genome-wide perturbation screens, we investigated the genetic dependencies of venetoclax and the BCL2/BCL2L1 dual inhibitor AZD4320. We identified the N6-methyladenosine (m6A) writer RBM15, and the Nucleosome Remodeling and Deacetylase (NuRD) complex interactor ZMYND8 as novel mediators of resistance to both venetoclax and AZD4320. Loss of RBM15 or ZMYND8 induced drug resistance, concurrent with alterations in BCL2 family expression and monocytic differentiation. Accordingly, in AML patient samples we found reduced expression of the respective m6a or NuRD complexes was significantly associated with monocytic differentiation and ex vivo resistance to the same drugs. These findings provide critical insights into previously undescribed mechanisms of BCL2 family inhibitor resistance in AML.
2026-04-09 | GSE294240 | GEO
Project description:Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. Kinome profiling of Molm14 cells, both NRAS WT and NRAS G12C, both treatment-naive and venetoclax resistant, additionally shows RAS upregulation with venetoclax resistance. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.
2026-06-15 | PXD068585 | Pride
Project description:The BET (bromodomain and extra terminal) protein family members including BRD4 bind to acetylated lysines on histones and regulate the expression of important oncogenes, e.g., MYC and BCL2. Here we demonstrate the sensitizing effects of the histone hyperacetylation inducing pan-histone deacetylase inhibitor (HDI) panobinostat (PS) on human AML blast progenitor cells (BPCs) to the BET protein inhibitor JQ1. Treatment with JQ1 but not its inactive enantiomer (R-JQ1) was highly lethal against AML BPCs expressing mutant NPM1c+ with or without co-expression of FLT3-ITD, or AML expressing MLL fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of MYC and BCL2, and reduced their levels in the AML cells. Co-treatment with JQ1 and the HDAC inhibitor panobinostat (PS) synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of MYC and BCL2, while increasing p21, BIM and cleaved PARP levels in the AML BPCs. Co-treatment with JQ1 and PS significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (p < 0.01). These findings highlight co-treatment with a BRD4 antagonist and an HDI as a potentially efficacious therapy of AML.
2014-01-01 | GSE51950 | GEO
Project description:Here, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and required for AML development/maintenance and leukemia stem cell (LSC) self-renewal, but is dispensable for normal hematopoiesis. ALKBH1 plays a pivotal role in regulating mitochondrion structure/functions and facilitating oxidative phosphorylation (OXPHOS) to generate energy for AML cell survival/proliferation. Mechanistically, we uncover that ALKBH1 specifically promotes 5-formylcytidine (f5C) formation in tRNAs to expand tRNA decoding capacity and promote translation of essential targets. This mechanism/phenomenon is termed “epitranscriptomic Midas touch”, which promotes expression of WDR43 and BCL2, two crucial targets of ALKBH1 in AML. ALKBH1 targeting markedly enhances BCL2 inhibitor (Venetoclax)’s efficacy in AML treatment. Collectively, our studies reveal the functional importance of a previously unappreciated signaling (i.e., ALKBH1/tRNA-f5C/WDR43/BCL2) in AML, and highlight the potential of targeting ALKBH1 for cancer therapy.
2025-07-23 | GSE260906 | GEO
Project description:Here, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and required for AML development/maintenance and leukemia stem cell (LSC) self-renewal, but is dispensable for normal hematopoiesis. ALKBH1 plays a pivotal role in regulating mitochondrion structure/functions and facilitating oxidative phosphorylation (OXPHOS) to generate energy for AML cell survival/proliferation. Mechanistically, we uncover that ALKBH1 specifically promotes 5-formylcytidine (f5C) formation in tRNAs to expand tRNA decoding capacity and promote translation of essential targets. This mechanism/phenomenon is termed “epitranscriptomic Midas touch”, which promotes expression of WDR43 and BCL2, two crucial targets of ALKBH1 in AML. ALKBH1 targeting markedly enhances BCL2 inhibitor (Venetoclax)’s efficacy in AML treatment. Collectively, our studies reveal the functional importance of a previously unappreciated signaling (i.e., ALKBH1/tRNA-f5C/WDR43/BCL2) in AML, and highlight the potential of targeting ALKBH1 for cancer therapy.
2025-07-23 | GSE260905 | GEO
Project description:Despite efficacy of FLT3 and BCL2 inhibition in acute myeloid leukemia (AML), relapse limits survival. Mutation status and AML monocytic differentiation are implicated in resistance. On-treatment tumor evolution may select for genetically distinct clones or shifts in differentiation not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of patients treated on a clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Git) to characterize immunophenotypic, transcriptional, and genetic clonal evolution on therapy. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, it selected for RAS mutations, RAS pathway activation and RAS-associated monocytic differentiation. In an in vitro model of monocytic differentiation associated with heightened RAS pathway activation, we demonstrated that MEK inhibition re-sensitized to Ven/Gilt. These data indicate RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to monocytic differentiation and can be overcome by RAS pathway inhibition.
2026-04-01 | GSE324062 | GEO
Project description:Treatment with Menin inhibitor (MI) disrupts interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, majority of patients with AML with MLLr or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin, or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in cell line or PD AML cell xenografts harboring MLL1r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLLr AML cells expressing FLT3 mutation, also CRISPR edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1r or mtNPM1.
2022-03-12 | GSE190719 | GEO
Project description:Menin inhibitors have demonstrated profound preclinical activity in MLL1-rearranged and NPM1 mutated AML and in this context, ziftomenib is a novel compound currently assessed in a clinical phase I/II trials. We assessed preclinical effects of ziftomenib and demonstrate profound synergy in combination with compounds targeting chromatin regulation and apoptosis including the BCL2 inhibitor venetoclax which was validated in primary AML samples and an MLL-r and NPM1 mutated AML xenograft model.
2023-05-01 | GSE228307 | GEO
Project description:Acute myeloid leukemia (AML) is an aggressive blood cancer with poor prognosis. We performed a comprehensive proteogenomic analysis of bone-marrow biopsies from 252 uniformly treated AML patients to elucidate the molecular pathophysiology of AML in order to inform future diagnostic and therapeutic approaches. In addition to in-depth quantitative proteomics, our analysis included cytogenetic and mutation profiling, and RNA sequencing. This identified five proteomic AML subtypes, each reflecting specific biological features spanning genomic boundaries. Two of these subtypes were correlated with patient outcome, but none exclusively associated with specific genomic aberrations. Remarkably, one subtype (Mito-AML), which was only captured in the proteome, was characterized by high expression of mitochondrial proteins and showed poor outcome, with reduced remission rate and shorter overall survival upon treatment with intensive induction chemotherapy. Functional analyses revealed that Mito-AML is metabolically wired towards stronger complex Idependent respiration and is more responsive to treatment with the BCL2-inhibitor venetoclax.
2022-03-08 | PXD028007 | Pride