近日，美国西奈山伊坎医学院Eirini P. Papapetrou及其研究小组发现，RAS突变的白血病干细胞驱动对venetoclax的临床耐药性。相关论文于2024年10月30日在线发表在《自然》杂志上。

通过使用人类白血病发生模型，研究人员首先表明RAS突变是必须在早期合作突变之后发生的晚期事件。研究人员提供了这一点的机制解释，指出突变的RAS需要特定转化已经携带早期驱动突变的髓单系前体细胞（粒细胞-单核细胞前体）。这表明，晚期白血病克隆可以起源于血液生成谱系中不同的细胞类型，而非祖先克隆。

此外，研究人员证明RAS突变的白血病干细胞（LSC）产生单核细胞疾病，这在对BCL2抑制剂venetoclax反应不佳的患者中常见。研究人员发现，RAS突变的LSC与RAS野生型LSC相比，BCL2家族基因表达发生变化，对venetoclax产生耐药性，从而导致临床耐药和复发并伴随单核细胞特征。这些发现表明，特定的基因驱动因素通过施加特定的LSC靶细胞限制，塑造了急性髓系白血病的非基因细胞层次结构，并对患者的治疗结果产生重要影响。

据了解，癌症驱动突变通常显示出不同的时间获取模式，但其生物学基础仍不清楚。RAS突变通常在急性髓系白血病的后期出现，发生在进展或复发/耐药疾病时。

附：英文原文

Title: RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax

Author: Sango, Junya, Carcamo, Saul, Sirenko, Maria, Maiti, Abhishek, Mansour, Hager, Ulukaya, Gulay, Tomalin, Lewis E., Cruz-Rodriguez, Nataly, Wang, Tiansu, Olszewska, Malgorzata, Olivier, Emmanuel, Jaud, Manon, Nadorp, Bettina, Kroger, Benjamin, Hu, Feng, Silverman, Lewis, Chung, Stephen S., Wagenblast, Elvin, Chaligne, Ronan, Eisfeld, Ann-Kathrin, Demircioglu, Deniz, Landau, Dan A., Lito, Piro, Papaemmanuil, Elli, DiNardo, Courtney D., Hasson, Dan, Konopleva, Marina, Papapetrou, Eirini P.

Issue&Volume: 2024-10-30

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.

DOI: 10.1038/s41586-024-08137-x

Source: https://www.nature.com/articles/s41586-024-08137-x