INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

作者：Wang, Ping; Ma, Dan; Wang, Jishi^*; Fang, Qin; Gao, Rui; Wu, Weibing; Cao, Lu; Hu, Xiuying; Zhao, Jiangyuan; Li, Yan

来源：Tumor Biology, 2016, 37(9): 12513-12523.

DOI：10.1007/s13277-016-5111-1

• INPP4B
• Cytarabine
• Resistance
• DNA repair

INPP4B has been recently shown to be a poor prognostic marker and confer chemo- or radio-resistance in AML cells, whereas, the underlying mechanisms remain unclear. Herein, we aimed to explore the possible mechanisms mediated the resistance to chemotherapy in AML. We found that INPP4B-mediated resistance to genotoxic drug, cytarabine, was accompanied by lower p-H2AX accumulation in KG-1 cells, and INPP4B knockdown evidently sensitized KG-1 cells to cytarabine, meanwhile, p-H2AX expression was increased dramatically. Then, we observed that INPP4B knockdown inhibited the loss of p-H2AX expression after cytarabine removal in INPP4B-silenced KG-1 cells, whereas, in control KG-1 cells, the expression of p-H2AX was reduced in a time-dependent manner. Next, INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM, p-BRCA1, p-ATR, and p-RAD51. Furthermore, nuclear localization of p65 was inhibited after INPP4B knockdown, and reactivation of p65 can rescue the INPP4B knockdown-induced inhibition of ATM, p-ATM, p-BRCA1, p-ATR, and p-RAD51. Finally, INPP4B expression was positively correlated with ATM expression in AML cells, both INPP4B knockdown and KU55933 can significantly sensitize primary myeloid leukemic cells to cytarabine treatment. @@@ Collectively, these data suggest that enhanced ATM-dependent DNA repair is involved in resistance to chemotherapy in INPP4B(high) AML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4B(high) AML.

• 出版日期2016-9
• 单位贵州医科大学