title: INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia.
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 INPP4BhighAML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4BhighAML.
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|Department of Pharmacy, Affiliated BaiYun Hospital of Guizhou Medical University, Guiyang, 550014, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China. wangjishi9646@163.com.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China. wangjishi9646@163.com.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China. wangjishi9646@163.com.
authors.forename: Jishi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Affiliated BaiYun Hospital of Guizhou Medical University, Guiyang, 550014, China.|Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Jiangyuan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.|Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China.|GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus; D000293:Adolescent; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D002648:Child; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D005260:Female; D006657:Histones / Q000032:analysis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D006657:Histones; D051996:Transcription Factor RelA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase
keywords: Cytarabine; DNA repair; INPP4B; Resistance