Transcriptional Signatures of the BCL2 Family in Acute Myeloid Leukaemia Treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE209822 | GEO | 2022/07/27
REPOSITORIES: GEO
Similar Datasets
Project description:Overexpression of antiapoptotic BCL2 family proteins occurs in various hematologic malignanices and contributes to leukemogenesis by inhibiting the apoptotic machinery of the cells. BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. To find additional hematologic entities with ectopic expression of BCL2 family members, we performed expression screening applying the LL-100 panel. Primary effusion lymphoma (PEL) and anaplastic large cell lymphoma (ALCL), 2/22 entities covered by this panel, stood out by high expression of MCL1 and low expression of BCL2. The MCL1 inhibitor AZD-5991 induced apoptosis in both malignancies suggesting that this BH3 mimetic might be efficient as drug for these diseases. The ALCL cell lines also expressed BCLXL and BCL2A1, both contributing to survival of the cells. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/AKT inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, providing an alternative to avoid thrombocytothemia, which is associated with the use of BCLXL inhibitors.
2021-12-31 | E-MTAB-10903 | biostudies-arrayexpress
Project description:Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
2022-04-09 | GSE182006 | GEO
Project description:Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
2022-04-09 | GSE181977 | GEO
Project description:Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
2022-04-09 | GSE182020 | GEO
Project description:Majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared to AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1 and c-Myc. Compared to AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. HHT treatment repressed enhancers and their BRD4 occupancy, as well as reduced levels of c-Myc, c-Myb, MCL1 and Bcl-xL. Consistent with this, co-treatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared to each agent alone, co-treatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.
2022-04-09 | GSE182018 | GEO
Project description:The aim is investigate the alterations in the transcriptome after combined inhibition of S100A9 and BCL2 in AML cell lines.
2023-12-01 | E-MTAB-13095 | biostudies-arrayexpress
Project description:Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for treatment of hematological malignancies.We here evaluated the expression of several spliceosome machinery components in primary multiple myeloma (MM) cells and the impact of splicing modulations on MM cell growth and viability.Our comprehensive gene expression analysis confirmed deregulation of spliceosome machinery components in MM cells compared to normal plasma cells (PCs) from healthy donors, while pharmacological and genetic modulation of splicing confirmed significant impact on growth and survival of MM cell lines and patient-derived malignant PCs. Transcriptomic analysis revealed deregulation of BCL2 family membersincluding decrease of proapoptotic long form of myeloid cell leukemia-1 (MCL1) expression in cells treated with splicing inhibitors. This caused a shift in the apoptotic priming resulting in improved BCL2-dependenceand increased sensitivity to Venetoclax, a BCL2 small molecule inhibitor, in vitro and in vivo. Overall, our data provide a rationale for supporting clinical use of splicing modulators as strategy to reprogram apoptotic dependencies, making MM patients more vulnerable to BCL2 inhibitors.
2022-02-08 | GSE167042 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive. In this study, by integrating ATACseq and RNAseq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A "B cell-like" epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B cell rather than plasma cell biology. Of note, a loss of a "B cell-like" epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in t(11;14) MM patients. To date, this is the first study in which both scATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.
2023-09-21 | GSE199373 | GEO
Project description:Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR/Cas9 screens across a broad range of therapies used in acute myeloid leukemia (AML) to identify genomic determinants of drug response. Our screens uncovered a selective dependency on RNA splicing factors whose loss preferentially synergized with the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augmented response to venetoclax in leukemia yet was completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition led to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. A novel inhibitor of splicing kinase families CLKs and DYRKs led to intron retention of key splicing factors identified from our screens, synergized with venetoclax, and overcame resistance to BCL2 inhibition. Our findings underscore the central importance of splicing in modulating apoptosis and provide a strategy to improve venetoclax-based treatments.
2022-10-31 | GSE199160 | GEO
Project description:BH3 mimetics are used as an efficient strategy to promote mitochondrial-dependent cell death in blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML, while various compounds targeting MCL1 are in clinical trials. Yet, drug resistance eventually ensues, highlighting the urgency to understand the underlying mechanisms. Our genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy regulators sensitizes AML to BH3 mimetics. One such regulator is Mitofusin-2 (MFN2), a GTPase that controls mitochondrial dynamics and the degradation of damaged mitochondria through mitophagy. Resistance to BH3 mimetics is accompanied by alterations in mitochondrial morphology, enhanced mitochondria-endoplasmic reticulum interactions, and augmented mitophagy flux. MFN2 inactivation, using a novel small molecule inhibitor, and pharmacologic inhibition of mitophagy synergizes with BH3 mimetics. Overall, targeting of mitophagy along with BCL2-family members is a promising strategy to overcome drug resistance in AML.
2023-07-10 | GSE182401 | GEO