RNA错误剪接的sf3b1突变模型揭示了UBA1作为骨髓增生异常肿瘤的治疗靶点

IF 13.4 1区 医学 Q1 HEMATOLOGY
Jonas Thier, Sophia Hofmann, Katharina M. Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C. Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G. Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P. Papapetrou, Eva Hellström-Lindberg, Pedro L. Moura, Vanessa Lundin
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引用次数: 0

摘要

剪接因子SF3B1基因(MDS-SF3B1)体细胞突变的骨髓增生异常综合征导致RNA剪接错误,红细胞发育不良,最终导致难治性贫血。由于错误剪接的复杂性及其在疾病精确模型中的评估,MDS-SF3B1的精准医学方法仍然具有挑战性。为了揭示新的RNA错误剪接事件,将来自MDS-SF3B1患者的等基因SF3B1K700E和SF3B1WT iPSC细胞系分化为造血细胞,并使用全长RNA测序通过无监督剪接事件分析进行分析。研究发现sf3b1k700e特异性的泛素样修饰物激活酶1 (UBA1)的错误剪接,该修饰物编码泛素化级联顶端的关键E1蛋白。UBA1错误剪接(UBA1ms)引入了蛋白质不稳定性并降低了总UBA1水平,使突变细胞对小分子UBA1抑制剂TAK-243敏感。来自MDS患者队列的CD34+ RNA测序数据分析证实,在MDS- sf3b1患者中存在独特且普遍存在的UBA1ms,而在其他剪接因子突变的MDS病例或健康对照中不存在UBA1ms。TAK-243选择性靶向MDS-SF3B1原代CD34+细胞,并在集落形成实验中减少突变细胞数量。相比之下,正常的造血祖细胞不受影响。总之,我们在这里将UBA1ms定义为sf3b1突变细胞中的一种新的治疗脆弱性,将UBA1抑制作为未来MDS-SF3B1治疗的潜在途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms

SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms

Myelodysplastic syndromes with somatic mutations in the splicing factor SF3B1 gene (MDS-SF3B1) result in RNA mis-splicing, erythroid dysplasia and ultimately refractory anemia. Precision medicine approaches for MDS-SF3B1 remain challenging due to both the complexity of the mis-splicing landscape and its evaluation in disease-accurate models. To uncover novel RNA mis-splicing events, isogenic SF3B1K700E and SF3B1WT iPSC lines from an MDS-SF3B1 patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified SF3B1K700E-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (UBA1), which encodes a key E1 protein at the apex of the ubiquitination cascade. UBA1 mis-splicing (UBA1ms) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34+ RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous UBA1ms in MDS-SF3B1 patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-SF3B1 primary CD34+ cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define UBA1ms as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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