HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation.
HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation.
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DOI：
10.1016/j.stem.2015.08.004
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发表时间：
2015-11-05
期刊：
影响因子：
23.9
通讯作者：
Kuo YH
中科院分区：
文献类型：
--
作者：
Qi J;Singh S;Hua WK;Cai Q;Chao SW;Li L;Liu H;Ho Y;McDonald T;Lin A;Marcucci G;Bhatia R;Huang WJ;Chang CI;Kuo YH
急性髓系白血病(AML)是由具有无限自我更新能力和对化疗耐药的白血病干细胞(LSCs)驱动和维持的。在初治AML中，肿瘤抑制基因TP53的突变相对较少；然而，P53可以通过翻译后机制进行调节。在这里，我们发现在Inv(16)+AML LSCs中，P53活性通过与CBFβ-SMMHC(CM)融合蛋白和组蛋白脱乙酰基酶8(HDAC8)的相互作用而被抑制。HDAC8异常去乙酰化P53，促进LSC转化和维持。HDAC8缺乏或使用HDAC8选择性抑制剂(HDAC8i)抑制可有效恢复P53的乙酰化和活性。重要的是，抑制HDAC8可以诱导inv(16)+AML CD34+细胞的凋亡，而不影响正常的造血干细胞。此外，体内HDAC8i给药大大减少了AML的繁殖，并取消了小鼠和患者来源的LSCs的白血病启动能力。这项研究阐明了HDAC8介导的P53失活机制促进LSC活性，并强调HDAC8抑制是选择性靶向inv(16)+LSCs的一种有前途的方法。
Acute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)+ AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16)+ AML CD34+ cells while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates a HDAC8-mediated p53-inactivating mechanism promoting LSC activity, and highlights HDAC8 inhibition as a promising approach to selectively target inv(16)+ LSCs.