Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.

IF 11.5 Q1 HEMATOLOGY Blood Cancer Discovery Pub Date : 2024-05-01 DOI:10.1158/2643-3230.BCD-23-0235
Thomas Köhnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti
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Abstract

Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant-specific therapeutic vulnerability in both premalignant CH and myeloid malignancy.

Significance: Mutant ASXL1 is a common driver of CH and myeloid malignancy. Using primary human HSPCs, we determine that truncated ASXL1 leads to redistribution of H2AK119Ub and may affect therapeutic vulnerability to PRC1 inhibition.

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人类 ASXL1 基因突变造血是由与 H2AK119 去泛素化异常有关的截短蛋白驱动的。
在髓系恶性肿瘤和恶性前克隆性造血(CH)中,额外性梳状突变 1(ASXL1)都会导致不良预后。然而,这些突变导致疾病发生的机制仍未得到解决,而突变特异性靶向治疗也仍未实现。为了解决这个问题,我们建立了一个人类疾病模型,该模型再现了从ASXL1突变CH到致死性髓系恶性肿瘤的疾病轨迹。我们证明,ASXL1突变会导致功能性截短蛋白的表达,并确定截短的ASXL1会导致抑制性染色质标记H2AK119Ub的全球重新分布、转座酶可访问染色质的增加以及髓系和干细胞基因表达程序的激活。最后,我们证明了H2AK119Ub水平与截短的ASXL1表达水平相关,并利用这一观察结果证明,抑制PRC1复合物可能是ASXL1突变体在恶性前CH和骨髓恶性肿瘤中的特异性治疗弱点。
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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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