Abstract A04: Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

IF 11.5 Q1 HEMATOLOGY

Blood Cancer Discovery Pub Date : 2023-05-01 DOI:10.1158/2643-3249.aml23-a04

Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard

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Abstract

Abstract 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 to identify genomic determinants of drug response. Our screens uncovered a selective dependency on RNA splicing factors whose loss preferentially enhanced response to 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 aberrant splicing of key splicing and apoptotic factors that synergized with venetoclax and overcame resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments. Citation Format: Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A04.

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摘要:RNA剪接的调节增强了白血病对BCL2抑制的应答

治疗耐药是癌症治疗中的一个重大挑战。在这里，我们在急性髓性白血病的广泛治疗中进行了CRISPR/Cas9筛选，以确定药物反应的基因组决定因素。我们的筛选揭示了对RNA剪接因子的选择性依赖，这些剪接因子的缺失优先增强了对BCL2抑制剂venetoclax的反应。剪接因子RBM10的缺失增强了白血病患者对venetoclax的反应，但对正常造血是完全必要的。RBM10和BCL2联合抑制导致细胞凋亡抑制剂XIAP的错误剪接和失活，以及BCL2A1(一种与venetoclax耐药有关的抗凋亡蛋白)的下调。剪接激酶家族CLKs和DYRKs的一种新型抑制剂导致关键剪接和凋亡因子的异常剪接，这些因子与venetoclax协同并克服了对BCL2抑制的抗性。我们的研究结果强调了剪接在调节治疗反应中的重要性，并提供了一种改进venetoclax治疗的策略。引文格式:Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard。RNA剪接调节增强白血病对BCL2抑制的应答[摘要]。摘自:AACR特别会议论文集:急性髓性白血病和骨髓增生异常综合征;2023年1月23-25日;费城(PA): AACR;血癌发现[j]; 2009;4(3 -增刊):摘要nr A04。

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来源期刊

Blood Cancer Discovery Multiple-

CiteScore

12.70

自引率

1.80%

发文量

139

期刊介绍： The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.