Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the KIT^D816V mutation in AML cells and contributed to support their cell proliferation and survival. Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KIT^D816V TF-1 cells. Downstream of KIT^D816V, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. Accordingly, STAT3 pharmacological inhibition or downregulation inhibited autophagy and reduced tumor growth both in vitro and in vivo. Taken together, our results support the notion that targeting autophagy or STAT3 opens up an exploratory pathway for finding new therapeutic opportunities for patients with CBF-AML or others malignancies with KIT^D816V mutations.

自噬与骨髓恶性肿瘤的存活和细胞死亡有关。因此，破解其在急性髓性白血病（AML）的不同遗传定义的亚型中的作用至关重要。在核心结合因子AML中经常检测到KIT受体酪氨酸激酶的激活突变，并与更大的复发风险相关。在本文中，我们报道了AML细胞中的KIT ^D816V突变显着增加了基础自噬，并有助于支持其细胞增殖和存活。关键自噬蛋白Atg12的失效大大降低了肿瘤负担，并改善了植入KIT ^D816V TF-1细胞的免疫受损NSG小鼠的存活率。KIT ^D816V的下游，STAT3，但不是AKT或ERK途径，被确定为自噬的主要调节因子。因此，STAT3药理学抑制或下调在体外和体内均抑制自噬并降低肿瘤生长。综上所述，我们的结果支持以下观点：靶向自噬或STAT3为CBF-AML或其他具有KIT ^D816V突变的恶性肿瘤患者寻找新的治疗机会开辟了探索途径。