Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway.
Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway.
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DOI：
10.1038/leu.2016.287
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发表时间：
2017-05
期刊：
影响因子：
11.4
通讯作者：
Zhang J
中科院分区：
文献类型：
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作者：
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 MM;Kuo PC;Nand S;Kini AR;Zhang J;Chen J;Zhu J;Zhang J
肿瘤坏死因子α诱导的RIP1/RIP3介导的坏死性下垂已被认为是治疗耐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，特别是M4和M5亚型，都能产生肿瘤坏死因子，并显示RIP1/RIP3/MLKL信号的基础水平激活，但不发生坏死性下垂。肿瘤坏死因子通过RIP1/RIP3信号通路阻止干扰素-γ信号的关键负调控因子SOCS1的降解。通过药理学和遗传学分析，我们发现RIP1/RIP3失活导致了SOCS1蛋白水平的降低和AML细胞的部分分化。RIP1/RIP3信号失活的急性髓系白血病细胞对干扰素-γ诱导分化的敏感性增加。RIP1/RIP3失活联合干扰素-γ处理可显著降低原代和原代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，当与其他分化诱导剂联合使用时，抑制RIP1/RIP3介导的坏死信号转导可能是治疗AML的一种新策略。
Tumor necrosis factor-α (TNF)-induced RIP1/RIP3-mediated necroptosis has been proposed to be 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.