In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target.

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2023-05-01 DOI:10.1158/2643-3230.BCD-22-0086
Ana Vujovic, Laura de Rooij, Ava Keyvani Chahi, He Tian Chen, Brian A Yee, Sampath K Loganathan, Lina Liu, Derek C H Chan, Amanda Tajik, Emily Tsao, Steven Moreira, Pratik Joshi, Joshua Xu, Nicholas Wong, Zaldy Balde, Soheil Jahangiri, Sasan Zandi, Stefan Aigner, John E Dick, Mark D Minden, Daniel Schramek, Gene W Yeo, Kristin J Hope
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引用次数: 1

Abstract

Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an in vivo two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9;NrasG12D AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven in vivo leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell-adapted in vivo CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML.

Significance: LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell-adapted in vivo CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. This article is highlighted in the In This Issue feature, p. 171.

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体内筛选揭示了白血病干细胞中普遍存在的RNA结合蛋白依赖性,并确定ELAVL1为治疗靶点。
急性髓性白血病(AML)是由白血病干细胞(LSC)引起的,其决定因素很难从造血干细胞(HSC)中辨别出来,也很难通过专注于一般细胞特性的方法来揭示。我们已经鉴定了一组在人类AML LSCs中选择性富集的RNA结合蛋白(RBP)。使用体内两步CRISPR-Cas9筛选来测定干细胞功能,我们在MLL-AF9中发现了32个对LSCs至关重要的RBP;NrasG12D AML。靶向关键命中RBP ELAVL1的功能丧失方法损害了LSC驱动的体内白血病重建,并选择性地耗尽了原始恶性细胞与健康细胞。综合多组学显示,分化、剪接和线粒体代谢是白血病ELAVL1 mRNA与线粒体输入蛋白TOMM34相互作用的关键特征,TOMM34是ELAVL1稳定的直接靶点,其抑制削弱AML的传播。总之,使用干细胞适应的体内CRISPR筛选,这项工作证明了RBPs作为LSCs的调节因子的普遍依赖性,并突出了它们作为AML治疗靶点的潜力。意义:LSC靶向治疗在AML中仍然是一个显著的未满足需求。我们开发了一种适用于干细胞的体内CRISPR筛选,以识别关键的LSC驱动因素。我们发现LSCs中广泛存在的RNA结合蛋白依赖性,包括ELAVL1,我们通过其对线粒体代谢的调节将其确定为一种新的治疗脆弱性。这篇文章在第171页的“本期”专题文章中有重点介绍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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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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