Suberoylanilide Hydroxamic Acid Induces Hypersensitivity to Radiation Therapy in Acute Myelogenous Leukemia Cells Expressing Constitutively Active FLT3 Mutants

Histone deacetylase inhibitors (HDIs) have shown promise as candidate radiosensitizer for many types of cancers. However, the mechanisms of action are not well understood, and whether they could have clinical impact on radiotherapy for leukemia is unclear. In this study, we demonstrate that suberoylanilide hydroxamic acid (SAHA) can increase radiosensitivity of acute myeloid leukemia (AML) cells through posttranslational modification of Rad51 protein responses and selective inhibition of the homology-directed repair (HDR) pathway. Our data also showed that AML cells with mutant, constitutively active FMS-like tyrosine kinase-3 (FLT3) were more radiation sensitive, caused by compromised non-homologous end joining (NHEJ) repair. Furthermore, SAHA-induced radiosensitization were enhanced in AML cells with expression of these FLT3 mutants. The results of this study suggest that SAHA, a recently approved HDI in clinical trials, may act as a candidate component for novel conditioning regimens to improve efficacy for AML patients undergoing radiotherapy and chemotherapy.

组蛋白去乙酰化酶抑制剂（Histone deacetylase inhibitors, HDIs）已被证实可作为多种癌症的候选放射增敏剂。然而，其具体作用机制尚未完全阐明，且这类抑制剂对白血病放射治疗是否具有临床价值仍不明确。本研究证实，辛二酰苯胺异羟肟酸（suberoylanilide hydroxamic acid, SAHA）可通过调控Rad51蛋白的翻译后修饰反应，并选择性抑制同源定向修复（homology-directed repair, HDR）通路，增强急性髓系白血病（acute myeloid leukemia, AML）细胞的放射敏感性。本研究数据同时显示，携带突变型、组成型激活型FMS样酪氨酸激酶3（FMS-like tyrosine kinase-3, FLT3）的AML细胞对放射线更为敏感，该现象源于非同源末端连接（non-homologous end joining, NHEJ）修复功能受损。此外，在表达上述FLT3突变体的AML细胞中，SAHA诱导的放射增敏效应进一步增强。本研究结果表明，SAHA作为一款近期获批且已进入临床试验的HDIs，有望成为新型预处理方案的候选组分，以提升接受放化疗的AML患者的治疗效果。