BH3模拟剂被用作诱导细胞死亡的有效策略，可用于治疗包括急性髓性白血病（AML）在内的多种血液肿瘤。Venetoclax，一种有效的BCL-2拮抗剂，在与低甲基化剂联合治疗AML时得到了临床应用。此外，还在研究MCL-1或双重BCL-2/BCL-xL拮抗剂。但是，对于单一或组合的BH3模拟剂治疗最终会出现耐药性。整合多个基因组范围的CRISPR/Cas9筛选发现，失去线粒体吞噬调节因子会使AML细胞对不同BCL-2家族成员的各种BH3模拟剂更为敏感。其中之一就是MFN2，其蛋白水平与AML患者的药物抗性呈正相关。MFN2的过度表达足以驱动AML对BH3模拟剂的耐药性。对BH3模拟剂的不敏感伴随着增强的线粒体-内质网相互作用和增强的线粒体吞噬流量，这是一种促进细胞存活的机制，可消除线粒体损伤。遗传学或药理学上靶向MFN2与BH3模拟剂结合起来可以通过障碍线粒体清除和增强AML中的凋亡作用来协同作用。

BH3-mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL-1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3-mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3-mimetics in AML. Insensitivity to BH3-mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux which acts as a pro-survival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3-mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.