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

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Tumor Biology

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 INPP4Bhigh AML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4Bhigh AML.

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References

  1. Woolley JF, Dzneladze I, Salmena L. Phosphoinositide signaling in cancer: INPP4B Akt(s) out. Trends in molecular medicine. 2015. doi:10.1016/j.molmed.2015.06.006.

    PubMed  Google Scholar 

  2. Ferron M, Vacher J. Characterization of the murine Inpp4b gene and identification of a novel isoform. Gene. 2006;376:152–61. doi:10.1016/j.gene.2006.02.022.

    Article  CAS  PubMed  Google Scholar 

  3. Agoulnik IU, Hodgson MC, Bowden WA, Ittmann MM. INPP4B: the new kid on the PI3K block. Oncotarget. 2011;2:321–8.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bertucci MC, Mitchell CA. Phosphoinositide 3-kinase and INPP4B in human breast cancer. Annals of the New York Academy of Sciences. 2013;1280:1–5. doi:10.1111/nyas.12036.

    Article  CAS  PubMed  Google Scholar 

  5. Gewinner C et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009;16:115–25. doi:10.1016/j.ccr.2009.06.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li H, Marshall AJ. Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: a distinct branch of PI3K signaling. Cellular signalling. 2015;27:1789–98. doi:10.1016/j.cellsig.2015.05.013.

    Article  PubMed  Google Scholar 

  7. Lundin C et al. High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with Down syndrome. Genes, chromosomes & cancer. 2012;51:196–206. doi:10.1002/gcc.20944.

    Article  CAS  Google Scholar 

  8. Barnache S, Le Scolan E, Kosmider O, Denis N, Moreau-Gachelin F. Phosphatidylinositol 4-phosphatase type II is an erythropoietin-responsive gene. Oncogene. 2006;25:1420–3. doi:10.1038/sj.onc.1209187.

    Article  CAS  PubMed  Google Scholar 

  9. Gasser JA, Inuzuka H, Lau AW, Wei W, Beroukhim R, Toker A. SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Molecular cell. 2014;56:595–607. doi:10.1016/j.molcel.2014.09.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Min JW et al. INPP4B-mediated tumor resistance is associated with modulation of glucose metabolism via hexokinase 2 regulation in laryngeal cancer cells. Biochemical and biophysical research communications. 2013;440:137–42. doi:10.1016/j.bbrc.2013.09.041.

    Article  CAS  PubMed  Google Scholar 

  11. Kim JS et al. Identification of inositol polyphosphate 4-phosphatase type II as a novel tumor resistance biomarker in human laryngeal cancer HEp-2 cells. Cancer Biol Ther. 2012;13:1307–18. doi:10.4161/cbt.21788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dzneladze I et al. INPP4B overexpression is associated with poor clinical outcome and therapy resistance in acute myeloid leukemia. Leukemia. 2015;29:1485–95. doi:10.1038/leu.2015.51.

    Article  CAS  PubMed  Google Scholar 

  13. Recher C. INPP4B, a new player in the chemoresistance of AML. Blood. 2015;125:2738–9. doi:10.1182/blood-2015-03-633669.

    Article  CAS  PubMed  Google Scholar 

  14. Rijal S et al. Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML. Blood. 2015;125:2815–24. doi:10.1182/blood-2014-09-603555.

    Article  CAS  PubMed  Google Scholar 

  15. Phillips ER, McKinnon PJ. DNA double-strand break repair and development. Oncogene. 2007;26:7799–808. doi:10.1038/sj.onc.1210877.

    Article  CAS  PubMed  Google Scholar 

  16. Ahn JW et al. SERBP1 affects homologous recombination-mediated DNA repair by regulation of CtIP translation during S phase. Nucleic acids research. 2015;43:6321–33. doi:10.1093/nar/gkv592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. D’Andrea AD. Targeting DNA repair pathways in AML. Best Pract Res Clin Haematol. 2010;23:469–73. doi:10.1016/j.beha.2010.09.005.

    Article  PubMed  Google Scholar 

  18. Ermolaeva MA, Dakhovnik A, Schumacher B. Quality control mechanisms in cellular and systemic DNA damage responses. Ageing research reviews. 2015;23:3–11. doi:10.1016/j.arr.2014.12.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Podhorecka M, Skladanowski A, Bozko P. H2AX phosphorylation: its role in DNA damage response and cancer therapy. Journal of nucleic acids. 2010. doi:10.4061/2010/920161.

    PubMed  PubMed Central  Google Scholar 

  20. Hahnel PS et al. Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy. Blood. 2014;123:2355–66. doi:10.1182/blood-2013-01-477620.

    Article  PubMed  Google Scholar 

  21. Khanna A. DNA damage in cancer therapeutics: a boon or a curse? Cancer Res. 2015;75:2133–8. doi:10.1158/0008-5472.CAN-14-3247.

    Article  CAS  PubMed  Google Scholar 

  22. Seedhouse CH. DNA repair contributes to the drug-resistant phenotype of primary acute myeloid leukaemia cells with FLT3 internal tandem duplications and is reversed by the FLT3 inhibitor PKC412. Leukemia. 2006;20:2130–6. doi:10.1038/sj.leu.2404439.

    Article  CAS  PubMed  Google Scholar 

  23. Esposito MT, So CW. DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance. Chromosoma. 2014;123:545–61. doi:10.1007/s00412-014-0482-9.

    Article  CAS  PubMed  Google Scholar 

  24. Ip LR et al. Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment. Oncotarget. 2015;6:10548–62.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shah NR, Mahmoudi M. The role of DNA damage and repair in atherosclerosis: a review. Journal of molecular and cellular cardiology. 2015;86:147–57. doi:10.1016/j.yjmcc.2015.07.005.

    Article  CAS  PubMed  Google Scholar 

  26. Rothkamm K, Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci U S A. 2003;100:5057–62. doi:10.1073/pnas.0830918100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu T, Huang J. Quality control of homologous recombination. Cellular and molecular life sciences : CMLS. 2014;71:3779–97. doi:10.1007/s00018-014-1649-5.

    Article  CAS  PubMed  Google Scholar 

  28. Krajewska M, Fehrmann RS, de Vries EG, van Vugt MA. Regulators of homologous recombination repair as novel targets for cancer treatment. Frontiers in genetics. 2015;6:96. doi:10.3389/fgene.2015.00096.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ward A, Khanna KK, Wiegmans AP. Targeting homologous recombination, new pre-clinical and clinical therapeutic combinations inhibiting RAD51. Cancer treatment reviews. 2015;41:35–45. doi:10.1016/j.ctrv.2014.10.006.

    Article  CAS  PubMed  Google Scholar 

  30. Faraoni I et al. BRCA1, PARP1 and gammaH2AX in acute myeloid leukemia: role as biomarkers of response to the PARP inhibitor olaparib. Biochimica et biophysica acta. 2015;1852:462–72. doi:10.1016/j.bbadis.2014.12.001.

    Article  CAS  PubMed  Google Scholar 

  31. Carvalho JF, Kanaar R. Targeting homologous recombination-mediated DNA repair in cancer. Expert opinion on therapeutic targets. 2014;18:427–58. doi:10.1517/14728222.2014.882900.

    Article  CAS  PubMed  Google Scholar 

  32. Kraft D et al. NF-kappaB-dependent DNA damage-signaling differentially regulates DNA double-strand break repair mechanisms in immature and mature human hematopoietic cells. Leukemia. 2015;29:1543–54. doi:10.1038/leu.2015.28.

    Article  CAS  PubMed  Google Scholar 

  33. Yarde DN et al. Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res. 2009;69:9367–75. doi:10.1158/0008-5472.CAN-09-2616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Volcic M, Karl S, Baumann B, Salles D, Daniel P, Fulda S, et al. NF-kappaB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes. Nucleic acids research. 2012;40:181–95. doi:10.1093/nar/gkr687.

    Article  CAS  PubMed  Google Scholar 

  35. Golding SE, Rosenberg E, Neill S, Dent P, Povirk LF, Valerie K. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res. 2007;67:1046–53. doi:10.1158/0008-5472.CAN-06-2371.

    Article  CAS  PubMed  Google Scholar 

  36. Barry SP, Townsend PA, Knight RA, Scarabelli TM, Latchman DS, Stephanou A. STAT3 modulates the DNA damage response pathway. International journal of experimental pathology. 2010;91:506–14. doi:10.1111/j.1365-2613.2010.00734.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Otterbein LE, Hedblom A, Harris C, Csizmadia E, Gallo D, Wegiel B. Heme oxygenase-1 and carbon monoxide modulate DNA repair through ataxia-telangiectasia mutated (ATM) protein. Proc Natl Acad Sci U S A. 2011;108:14491–6. doi:10.1073/pnas.1102295108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kodiha M, Stochaj U. Nuclear transport: a switch for the oxidative stress-signaling circuit? Journal of signal transduction. 2012;2012:208650. doi:10.1155/2012/208650.

    Article  PubMed  Google Scholar 

  39. Zhang J, Hug BA, Huang EY, et al. Oligomerization of ETO is obligatory for corepressor interaction. Mol Cell Biol. 2001;21(1):156–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Buschfort-Papewalis C, Moritz T, Liedert B, Thomale J. Down-regulation of DNA repair in human CD34(+) progenitor cells corresponds to increased drug sensitivity and apoptotic response. Blood. 2002;100:845–53. doi:10.1182/blood-2002-01-0022.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported, in part, by the National Natural Science Foundation of China (nos. 81070444, 81270636, 81360501, and 81470006), International Cooperation Project of Guizhou Province (no. 2011-7010), Social Project of Guizhou Province (no. 2011-3012), Provincial Government Special Fund of Guizhou Province (no. 2010-84), and Project of Science and Technology Bureau of Guiyang City (no. [2012103-36]).

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Authors and Affiliations

  1. Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Ping Wang, Dan Ma, Jishi Wang, Rui Gao, Weibing Wu, Xiuying Hu, Jiangyuan Zhao & Yan Li

  2. Key Laboratory of Hematological Disease Diagnostic and Treat Centre of GuiZhou Province, Guiyang, 550004, China

    Ping Wang, Dan Ma, Jishi Wang, Rui Gao, Weibing Wu, Xiuying Hu, Jiangyuan Zhao & Yan Li

  3. GuiZhou Province Hematopoietic Stem Cell Transplantation Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Ping Wang, Jishi Wang, Rui Gao, Weibing Wu, Xiuying Hu, Jiangyuan Zhao & Yan Li

  4. Department of Pharmacy, Affiliated BaiYun Hospital of Guizhou Medical University, Guiyang, 550014, China

    Dan Ma & Qin Fang

  5. Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China

    Qin Fang & Lu Cao

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  1. Ping Wang
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Correspondence to Jishi Wang.

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Wang, P., Ma, D., Wang, J. et al. INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia. Tumor Biol. 37, 12513–12523 (2016). https://doi.org/10.1007/s13277-016-5111-1

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