髓系白血病
癌症研究
HDAC8型
白血病
下调和上调
交易激励
酪氨酸激酶
Fms样酪氨酸激酶3
医学
生物
突变
组蛋白脱乙酰基酶
免疫学
内科学
组蛋白
受体
遗传学
转录因子
基因
作者
Jun Long,Mingyuan Jia,Weiyue Fang,Xinjie Chen,Lili Mu,Zhongyu Wang,Yan Shen,Rufang Xiang,Lining Wang,Xuan Wang,Chuanhe Jiang,Jieling Jiang,Wenjun Zhang,Yidan Sun,Chang Li,Wenhui Gao,Ying Wang,Junmin Li,Dengli Hong,Aibin Liang,Jiong Hu
出处
期刊:Blood
[American Society of Hematology]
日期:2020-02-13
卷期号:135 (17): 1472-1483
被引量:62
标识
DOI:10.1182/blood.2019003538
摘要
Abstract Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25% to 30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, they cannot eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1- and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKI treatment. Genetic or pharmacological inhibition of HDAC8 reactivates p53, abrogates leukemia maintenance, and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient–derived xenograft models, the combination of FLT3 TKI (AC220) and an HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase–activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation is an important mechanism to resist TKIs and promote leukemia maintenance and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation–harboring leukemias.
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