Mamdouh Ahmed M, Olesinski Elyse A, Lim Fang Qi, Jasdanwala Shaista, Mi Yang, Lin Nicole Si En, Liang Daniel Tan En, Chitkara Nishtha, Hogdal Leah, Lindsley R Coleman, Letai Anthony, Itahana Koji, Bhatt Shruti
Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore.
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
bioRxiv. 2025 Aug 31:2025.08.28.672283. doi: 10.1101/2025.08.28.672283.
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. mutations define one of the most lethal subtypes of acute myeloid leukemia (AML), driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in mutant/deficient AML compared to wild-type AML. Functionally, mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy - decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this "post-MOMP brake" is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
急性髓系白血病（AML）是一种异质性疾病，其特征是存在广泛的分子改变，这些改变会影响临床结局。 突变定义了急性髓系白血病（AML）最致命的亚型之一，导致对几乎所有可用治疗方式产生耐药性，包括维奈克拉加阿扎胞苷（VenAza）。然而，这种耐药性的分子基础，除了影响BCL-2家族基因的反式激活外，仍然难以捉摸。在这里，我们证明与野生型AML相比，VenAza治疗导致 突变/缺陷型AML中p53信号通路的转录上调减少。在功能上， 突变/缺陷型AML在诱导凋亡方面表现出选择性失败，而不是G1期阻滞或衰老受损。尽管在 突变的同基因AML细胞中抑制了促凋亡的BAX并选择性富集了MCL-1，但BIM的代偿性上调保留了功能性线粒体膜通透性转换（MOMP）。基线时的 突变原发性AML肿瘤也保留了MOMP的能力。相反， 突变型AML在VenAza治疗后表现出caspase-3/7激活的破坏以逃避凋亡——使凋亡的线粒体阶段和执行阶段脱钩。重要的是，这种“MOMP后制动”不是旁观者效应，而是 突变/缺陷型AML中VenAza和化疗耐药性的驱动因素。这一先前未被认识的机制见解将焦点从 突变型AML中的线粒体启动转移到终末半胱天冬酶阻断，并为迫切需要的在凋亡执行点重新激发凋亡的治疗策略打开了大门。
