FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia
FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia
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FLT3 抑制通过 FOXO 上调 HDAC8，使 p53 失活并促进 FLT3-ITD 急性髓系白血病的维持
DOI：
10.1182/blood.2019003538
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发表时间：
2020-04-23
期刊：
影响因子：
20.3
通讯作者：
Hu, Jiong
中科院分区：
文献类型：
--
作者：
Long, Jun;Jia, Ming-Yuan;Hu, Jiong
FMS样受体酪氨酸激酶-3（FLT 3）内的内部串联重复（ITD）突变可在高达25%至30%的急性髓性白血病（AML）患者中发现，并导致预后不良。尽管FLT 3酪氨酸激酶抑制剂（TKI）已显示出临床反应，但它们不能消除原始FLT 3-ITD+ AML细胞，这是复发的潜在来源。因此，阐明FLT 3-ITD+ AML维持和耐药性的机制对于开发新的有效治疗策略至关重要。在这里，我们证明FLT 3抑制诱导组蛋白脱乙酰酶8（HDAC 8）上调通过FOXO 1和FOXO 3介导的反式激活FLT 3-ITD+ AML细胞。上调的HDAC 8使p53脱乙酰化和失活，导致白血病维持和TKI治疗后的耐药性。HDAC 8的遗传或药理学抑制可重新激活p53，消除白血病维持，并显著增强TKI介导的FLT 3-ITD+ AML细胞消除。重要的是，在FLT 3-ITD+ AML患者来源的异种移植物模型中，FLT 3 TKI（AC 220）和HDAC 8抑制剂（22 d）的组合显著抑制白血病进展并有效减少原始FLT 3-ITDv AML细胞。此外，我们将这些发现扩展到携带另一种酪氨酸激酶激活突变的AML亚型。总之，我们的研究表明HDAC 8上调是抵抗TKI和促进白血病维持的重要机制，并表明HDAC 8抑制与TKI治疗相结合可能是治疗FLT 3-ITD+ AML和其他携带酪氨酸激酶突变的白血病的有希望的策略。
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-ITDv 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.