Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition.

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2024-09-03 DOI:10.1158/2643-3230.BCD-23-0230
Martina Sarchi, Courtnee A Clough, Edie I Crosse, Jason Kim, Laura D Baquero Galvis, Nelli Aydinyan, Rachel Wellington, Feini Yang, Anna Gallì, J Philip Creamer, Sintra Stewart, Robert K Bradley, Luca Malcovati, Sergei Doulatov
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Abstract

Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant immunophenotypic HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSPCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition. Significance: In this study, we engineer precise SF3B1 mutations in human HSPCs and identify CHK1 inhibition as a selective vulnerability promoted by mis-splicing of mitotic regulators. These findings uncover the mis-splicing program induced by mutant SF3B1 in human HSPCs and show that it can be therapeutically targeted by clinical CHK1 inhibitors.

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有丝分裂调节因子的错误拼接使 SF3B1 基因突变的人类造血干细胞对 CHK1 抑制作用敏感。
剪接因子SF3B1突变是骨髓性肿瘤中常见的体细胞病变,它通过诱导目标基因的错误剪接而转化造血干细胞(HSCs)。然而,SF3B1突变对人类造血干细胞的分子和功能影响仍不清楚。在这里,我们通过对原代CD34+细胞中SF3B1 K700E突变的精确基因编辑,确定了人类造血干细胞中的错误剪接程序是一个可靶向的弱点。突变的 SF3B1 诱导了普遍的错误剪接,并降低了调控有丝分裂和基因组维护的基因的表达,从而导致分化改变、G2/M 进展延迟以及对 CHK1 抑制(CHK1i)的高度敏感性。有丝分裂调节因子 BUBR1 和 CDC27 的错误拼接或表达减少会延迟 G2/M 过渡并提高对 CHK1i 的敏感性。临床用 CHK1i prexasertib 可选择性地靶向 SF3B1 突变的造血干细胞,并抑制其体内移植。这些研究结果表明,SF3B1突变造血干细胞中有丝分裂调节因子的错误拼接是药理CHK1抑制剂可靶向的弱点。
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来源期刊
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.
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