RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

IF 50.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Nature Pub Date : 2024-10-30 DOI:10.1038/s41586-024-08137-x
Junya Sango, Saul Carcamo, Maria Sirenko, Abhishek Maiti, Hager Mansour, Gulay Ulukaya, Lewis E. Tomalin, Nataly Cruz-Rodriguez, Tiansu Wang, Malgorzata Olszewska, Emmanuel Olivier, Manon Jaud, Bettina Nadorp, Benjamin Kroger, Feng Hu, Lewis Silverman, Stephen S. Chung, Elvin Wagenblast, Ronan Chaligne, Ann-Kathrin Eisfeld, Deniz Demircioglu, Dan A. Landau, Piro Lito, Elli Papaemmanuil, Courtney D. DiNardo, Dan Hasson, Marina Konopleva, Eirini P. Papapetrou
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Abstract

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1,2,3,4,5,6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte–monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.

Abstract Image

RAS突变的白血病干细胞导致了对Venetoclax的临床耐药性
癌症驱动基因突变常常表现出不同的时间获得模式,但其生物学基础(如果有的话)仍然未知。RAS突变总是发生在急性髓性白血病的晚期,即疾病进展或复发/难治时1,2,3,4,5,6。在此,我们利用人类白血病发病模型,首次证明 RAS 基因突变是必须发生的晚期事件,需要接替早期的合作突变。我们从机理上解释了这一点,即突变的 RAS 需要特异性地转化携带先前获得的驱动基因突变的骨髓单核细胞系(粒细胞-单核细胞祖细胞)的承诺祖细胞,这表明晚期白血病克隆可以起源于造血系统中不同于祖先克隆的细胞类型。此外,我们还证明了RAS突变的白血病干细胞(LSCs)会导致单核细胞疾病,这在对BCL2抑制剂venetoclax治疗反应不佳的患者中经常可以观察到。我们的研究表明,这是因为RAS突变型白血病干细胞与RAS野生型白血病干细胞不同,它们的BCL2家族基因表达发生了改变,并对venetoclax产生耐药性,从而导致临床耐药和具有单核细胞特征的复发。我们的研究结果表明,特定的遗传驱动因素通过对LSC靶细胞施加特定的限制,塑造了急性髓性白血病的非遗传细胞层次结构,并对患者的治疗结果产生了至关重要的影响。
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
Nature
Nature 综合性期刊-综合性期刊
CiteScore
90.00
自引率
1.20%
发文量
3652
审稿时长
3 months
期刊介绍: Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.
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