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

Content Provider	Springer Nature Link
Author	Wang, Ping Ma, Dan Wang, Jishi Fang, Qin Gao, Rui Wu, Weibing Cao, Lu Hu, Xiuying Zhao, Jiangyuan Li, Yan
Copyright Year	2016
Abstract	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.
Starting Page	12513
Ending Page	12523
Page Count	11
File Format	PDF
ISSN	10104283
Journal	Tumor Biology
Volume Number	37
Issue Number	9
e-ISSN	14230380
Language	English
Publisher	Springer Netherlands
Publisher Date	2016-06-24
Publisher Place	Dordrecht
Access Restriction	Subscribed
Subject Keyword	INPP4B Cytarabine Resistance DNA repair Cancer Research
Content Type	Text
Resource Type	Article
Subject	Medicine Cancer Research

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