Xin J, You D, Breslin P, Li J, Zhang J, Wei W, Cannova J, Volk A, Gutierrez R, Xiao Y, Ni A, Ng G, Schmidt R, Xia Z, Pan J, Chen H, Patel M M, Kuo P C, Nand S, Kini A R, Zhang J, Chen J, Zhu J, Zhang J
Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
Research and Development Service, Hines VA Hospital, Hines, IL, USA.
Leukemia. 2017 May;31(5):1154-1165. doi: 10.1038/leu.2016.287. Epub 2016 Oct 17.
Tumor necrosis factor-α (TNF-α)-induced RIP1/RIP3 (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3)-mediated necroptosis has been proposed as an alternative strategy for treating apoptosis-resistant leukemia. However, we found that most acute myeloid leukemia (AML) cells, especially M4 and M5 subtypes, produce TNF and show basal level activation of RIP1/RIP3/MLKL signaling, yet do not undergo necroptosis. TNF, through RIP1/RIP3 signaling, prevents degradation of SOCS1, a key negative regulator of interferon-γ (IFN-γ) signaling. Using both pharmacologic and genetic assays, we show here that inactivation of RIP1/RIP3 resulted in reduction of SOCS1 protein levels and partial differentiation of AML cells. AML cells with inactivated RIP1/RIP3 signaling show increased sensitivity to IFN-γ-induced differentiation. RIP1/RIP3 inactivation combined with IFN-γ treatment significantly attenuated the clonogenic capacity of both primary AML cells and AML cell lines. This combination treatment also compromised the leukemogenic ability of murine AML cells in vivo. Our studies suggest that inhibition of RIP1/RIP3-mediated necroptotic signaling might be a novel strategy for the treatment of AML when combined with other differentiation inducers.
肿瘤坏死因子-α（TNF-α）诱导的RIP1/RIP3（受体相互作用蛋白激酶1/受体相互作用蛋白激酶3）介导的坏死性凋亡已被提出作为治疗抗凋亡白血病的一种替代策略。然而，我们发现大多数急性髓系白血病（AML）细胞，尤其是M4和M5亚型，会产生TNF并显示出RIP1/RIP3/MLKL信号的基础水平激活，但不会发生坏死性凋亡。TNF通过RIP1/RIP3信号传导，阻止干扰素-γ（IFN-γ）信号的关键负调节因子SOCS1的降解。通过药理学和遗传学分析，我们在此表明RIP1/RIP3的失活导致SOCS1蛋白水平降低以及AML细胞的部分分化。RIP1/RIP3信号失活的AML细胞对IFN-γ诱导的分化表现出更高的敏感性。RIP1/RIP3失活与IFN-γ治疗相结合显著减弱了原代AML细胞和AML细胞系的克隆形成能力。这种联合治疗也损害了小鼠AML细胞在体内的致白血病能力。我们的研究表明，抑制RIP1/RIP3介导的坏死性凋亡信号传导可能是一种与其他分化诱导剂联合使用时治疗AML的新策略。
