Transcriptional and phenotypic heterogeneity underpinning venetoclax resistance in AML.
Transcriptional and phenotypic heterogeneity underpinning venetoclax resistance in AML.
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转录和表型异质性是 AML 中维奈托克耐药性的基础。
DOI：
10.1101/2024.01.27.577579
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Chen,Ken
中科院分区：
文献类型：
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作者：
Mohanty,Vakul;Baran,Natalia;Huang,Yuefan;Ramage,CassandraL;Cooper,LaurieM;He,Shan;Iqbal,Ramiz;Daher,May;CTD2ResearchNetwork;Tyner,JeffreyW;Mills,GordonB;Konopleva,Marina;Chen,Ken
Venetoclax BCL 2抑制剂与低甲基化药物联合使用代表了不适合强化化疗的老年AML患者诱导治疗的基石。与其他靶向治疗一样，基于维奈托克的治疗也存在先天性和获得性耐药性。虽然已经确定了几种耐药机制，但对患者人群中耐药机制的异质性了解甚少。在这里，我们利用AML患者的转录组学和离体药物反应数据的综合分析来鉴定四个转录上不同的VEN耐药簇（VR_C1-4），其具有不同的表型、遗传和药物反应模式。VR_C1的特征在于富集分化的单核细胞样和cDC样母细胞、PI 3 K-AKT-mTOR信号传导轴的转录激活和能量代谢途径。它们显示对mTOR和CDK抑制的敏感性。VR_C2富含NRAS突变，并与HOX表达的独特转录抑制相关。VR_C3的特征是TP 53突变富集和细胞毒性T细胞的较高浸润。该簇显示红系标志物的转录表达，表明肿瘤细胞模拟红系分化、JAK-STAT信号传导的激活和对JAK抑制的敏感性，其在一个子集的病例中与维奈托克协同作用。VR_C4与维奈托克敏感的患者共享转录相似性，具有干扰素信号的适度过度表达。他们的特征还在于DNMT 3A突变率高。最后，我们将维奈托克耐药状态投射到单细胞上，该单细胞来自在维奈托克治疗下复发的患者，该患者在肿瘤中捕获多种耐药状态，并且在维奈托克选择下其丰度发生变化，这表明单个肿瘤可能由模拟多个VR_C的细胞组成，这些细胞有助于肿瘤内异质性。总之，我们的研究结果提供了一种策略来评估维奈托克耐药机制的肿瘤间和肿瘤内异质性，并提供了对BCL 2抑制剂治疗失败患者的进一步管理方法的见解。
The venetoclax BCL2 inhibitor in combination with hypomethylating agents represents a cornerstone of induction therapy for older AML patients, unfit for intensive chemotherapy. Like other targeted therapies, venetoclax-based therapies suffer from innate and acquired resistance. While several mechanisms of resistance have been identified, the heterogeneity of resistance mechanism across patient populations is poorly understood. Here we utilized integrative analysis of transcriptomic and ex-vivo drug response data in AML patients to identify four transcriptionally distinct VEN resistant clusters (VR_C1–4), with distinct phenotypic, genetic and drug response patterns. VR_C1 was characterized by enrichment for differentiated monocytic- and cDC-like blasts, transcriptional activation of PI3K-AKT-mTOR signaling axis, and energy metabolism pathways. They showed sensitivity to mTOR and CDK inhibition. VR_C2 was enriched for NRAS mutations and associated with distinctive transcriptional suppression of HOX expression. VR_C3 was characterized by enrichment for TP53 mutations and higher infiltration by cytotoxic T cells. This cluster showed transcriptional expression of erythroid markers, suggesting tumor cells mimicking erythroid differentiation, activation of JAK-STAT signaling, and sensitivity to JAK inhibition, which in a subset of cases synergized with venetoclax. VR_C4 shared transcriptional similarities with venetoclax-sensitive patients, with modest over-expression of interferon signaling. They were also characterized by high rates of DNMT3A mutations. Finally, we projected venetoclax-resistance states onto single cells profiled from a patient who relapsed under venetoclax therapy capturing multiple resistance states in the tumor and shifts in their abundance under venetoclax selection, suggesting that single tumors may consist of cells mimicking multiple VR_Cs contributing to intra-tumor heterogeneity. Taken together, our results provide a strategy to evaluate inter- and intra-tumor heterogeneity of venetoclax resistance mechanisms and provide insights into approaches to navigate further management of patients who failed therapy with BCL2 inhibitors.