Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax
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ABSTRACT:
PROVIDER: PRJNA702777 | ENA |
REPOSITORIES: ENA
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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:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
2019-05-03 | GSE125403 | GEO
Project description:Targeting mitochondrial structure sensitizes AML to Venetoclax
| PRJNA516226 | ENA
Project description:Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment
| PRJNA1113589 | ENA
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: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 | GSE199159 | GEO
Project description:AMPK activation enhances apoptotic priming and BCL2 dependence via PERK phosphorylation
| PRJNA623197 | ENA
Project description:Activation of the MYC oncogene is common in B-cell lymphomas, and frequently associated with compensatory events that dampen Myc-induced apoptosis, such as over-expression of anti-apoptotic Bcl2-family proteins. For example, concurrent translocations of MYC and BCL2 in a subset of Diffuse large B-cell lymphoma (DLBCL) lead to the high-grade “double-hit” lymphoma subtype (DHL), characterized by dismal prognosis in the face of current front-line regimens, thus calling for the pursuit of tailored therapeutic strategies. Here, we show that Myc and Bcl2 modulate the sensitivity of B-cells to IACS-010759, a selective inhibitor of mitochondrial respiratory complex I. Myc activation in non-transformed lymphoid precursors suppressed endogenous Bcl2 and sensitized the cells to IACS-010759-induced apoptosis. Treatment with the Bcl2 inhibitor venetoclax also sensitized to IACS-010759, while overexpression of Bcl-2 was protective. IACS-010759 engaged an ATF4-driven Integrated Stress Response (ISR) with dual anti- and pro-apoptotic effects, the latter mediated by the CHOP transcription factor, which contributed to selective killing of Myc-overexpressing cells. In line with the above data, IACS-010759 and venetoclax synergized in killing human DHL cells, and showed strong combinatorial effects in a pre-clinical setting. In a Bcl2-negative Burkitt’s lymphoma cell line, instead, IACS-010759 synergized with the Mcl-1 inhibitor S63845. Altogether, our data point to the combination of IACS-010759 with distinct Bcl2-family inhibitors for therapeutic reactivation of the intrinsic apoptotic pathway in Myc-associated B-cell lymphomas
2022-03-01 | GSE149073 | GEO
Project description:Enhancer-dependence of gene expression increases with developmental age
| PRJNA448883 | ENA
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