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Mechanisms of resistance

Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia

Leukemia volume 34, pages 1816–1827 (2020)Cite this article

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Abstract

TP53 mutations (TP53mut) in AML patients associate with poor prognosis that may affect therapy and outcome. In addition to TP53 mut patients, TCGA AML patient sequencing data show that there are around 3% of patients have detectable low-frequency TP53mut reads. Importantly, these patients showed worse outcome as compared with the TP53 wild type (TP53wt) patients. We have studied the effect of low-frequency TP53mut in two AML cell lines, OCI-AML2 and MV4–11. Both cells have low-frequency single hotspot TP53mut. Interestingly, the resistant cells derived from both lines have homogeneous TP53mut. TP53mut clones isolated from the parental cells also show increased chemoresistance potential and have higher population of leukemia stem cell (LSC) maker positive cells, a characteristic of chemoresistant cells. When mixed with TP53wt cells, the TP53mut cells show survival advantage suggesting its potential to develop chemoresistance. We previously showed that histone deacetylase inhibitor Romidepsin can re-sensitize chemoresistant cells by eradicating LSC marker positive cells. Here we further show that Romidepsin can reactivate p53 targeted genes which are dysregulated in TP53mut cells and preferentially targets TP53mut subpopulation. Therefore, our study shows that low-frequency TP53mut is linked to chemoresistance and sheds light on therapeutic strategies for treatments on chemoresistance.

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Fig. 1: Lower p21 expressions were correlated with drug resistance.
Fig. 2: AML cells with TP53mut were significantly enriched after chemo drug selection.
Fig. 3: Cells with TP53mut have survival advantage under drug pressure and have higher leukemia stem cells percentage.
Fig. 4: Decrease of p53 target gene GADD45A also contributes to drug resistance.
Fig. 5: p53 mutation causes a reduction of p53 recruitment at both p21 and GADD45A promoters and leading to a decrease of histone acetylation at these regions.
Fig. 6: Romidepsin can restore genes dysregulated by p53 mutation by increase histone acetylation and preferentially targets TP53mut cells.

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  • 01 April 2020

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References

  1. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552–5.

    Article  CAS  Google Scholar 

  2. Soussi T. The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann NY Acad Sci. 2000;910:121–37. discussion 137–9.

    Article  CAS  Google Scholar 

  3. May P, May E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene. 1999;18:7621–36.

    Article  CAS  Google Scholar 

  4. Waga S, Hannon GJ, Beach D, Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature. 1994;369:574–8.

    Article  CAS  Google Scholar 

  5. Nguyen KT, Liu B, Ueda K, Gottesman MM, Pastan I, Chin KV. Transactivation of the human multidrug resistance (MDR1) gene promoter by p53 mutants. Oncol Res. 1994;6:71–7.

    CAS  PubMed  Google Scholar 

  6. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9:1799–805.

    CAS  PubMed  Google Scholar 

  7. Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992;71:587–97.

    Article  CAS  Google Scholar 

  8. el-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B. Definition of a consensus binding site for p53. Nat Genet. 1992;1:45–9.

    Article  CAS  Google Scholar 

  9. Levine AJ, Oren M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58.

    Article  CAS  Google Scholar 

  10. Yue X, Zhao Y, Xu Y, Zheng M, Feng Z, Hu W. Mutant p53 in cancer: accumulation, gain-of-function, and therapy. J Mol Biol. 2017;429:1595–606.

    Article  CAS  Google Scholar 

  11. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17.

    Article  CAS  Google Scholar 

  12. Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26:199–212.

    Article  Google Scholar 

  13. Shetzer Y, Molchadsky A, Rotter V. Oncogenic mutant p53 gain of function nourishes the vicious cycle of tumor development and cancer stem-cell formation. Cold Spring Harb Perspect Med. 2016;6:1–20.

  14. Koifman G, Shetzer Y, Eizenberger S, Solomon H, Rotkopf R, Molchadsky A, et al. A mutant p53-dependent embryonic stem cell gene signature is associated with augmented tumorigenesis of stem cells. Cancer Res. 2018;78:5833–47.

    CAS  PubMed  Google Scholar 

  15. Chen S, Yu H, Kobayashi M, Gao R, Boswell H, Liu Y. Gain-of-function mutant p53 enhances hematopoietic stem cell self-renewal. Blood. 2014;124:260.

  16. Solomon H, Dinowitz N, Pateras IS, Cooks T, Shetzer Y, Molchadsky A, et al. Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. Oncogene. 2018;37:1669–84.

    Article  CAS  Google Scholar 

  17. Bush JA, Li G. Cancer chemoresistance: the relationship between p53 and multidrug transporters. Int J Cancer. 2002;98:323–30.

    Article  CAS  Google Scholar 

  18. Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994;84:3148–57.

    Article  CAS  Google Scholar 

  19. Prokocimer M, Molchadsky A, Rotter V. Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy. Blood. 2017;130:699–712.

    Article  CAS  Google Scholar 

  20. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl J Med. 2013;368:2059–74.

    Article  Google Scholar 

  21. Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125:1367–76.

    Article  CAS  Google Scholar 

  22. Yan B, Chen Q, Shimada K, Tang M, Li H, Gurumurthy A, et al. Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia. Leukemia. 2019;33:931–44.

    Article  CAS  Google Scholar 

  23. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012;7:562–78.

    Article  CAS  Google Scholar 

  24. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  Google Scholar 

  25. Jian W, Yan B, Huang S, Qiu Y. Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly. Faseb J. 2017;31:4104–16.

    Article  CAS  Google Scholar 

  26. Yang H, Yan B, Liao D, Huang S, Qiu Y. Acetylation of HDAC1 and degradation of SIRT1 form a positive feedback loop to regulate p53 acetylation during heat-shock stress. Cell Death Dis. 2015;6:e1747.

    Article  CAS  Google Scholar 

  27. Gorospe M, Wang X, Holbrook NJ. Functional role of p21 during the cellular response to stress. Gene Expr. 1999;7:377–85.

    CAS  PubMed  Google Scholar 

  28. el-Deiry WS, Harper JW, O’Connor PM, Velculescu VE, Canman CE, Jackman J, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54:1169–74.

    CAS  PubMed  Google Scholar 

  29. Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47:D941–7.

    Article  CAS  Google Scholar 

  30. Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res. 2000;60:6788–93.

    CAS  PubMed  Google Scholar 

  31. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.

    Article  Google Scholar 

  32. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    Article  Google Scholar 

  33. Pfister NT, Prives C. Transcriptional regulation by wild-type and cancer-related mutant forms of p53. Cold Spring Harb Perspect Med. 2017;7:1–26.

  34. Loizou E, Banito A, Livshits G, Ho YJ, Koche RP, Sanchez-Rivera FJ, et al. A gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor FOXH1. Cancer Discov. 2019;9:962–79.

  35. Salvador JM, Brown-Clay JD, Fornace AJ Jr. Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv Exp Med Biol. 2013;793:1–19.

    Article  CAS  Google Scholar 

  36. Hoffman B, Liebermann DA. Gadd45 in modulation of solid tumors and leukemia. Adv Exp Med Biol. 2013;793:21–33.

    Article  CAS  Google Scholar 

  37. Wang S, Gribskov M, Hazbun TR, Pascuzzi PE. CellMiner companion: an interactive web application to explore CellMiner NCI-60 data. Bioinformatics. 2016;32:2399–401.

    Article  CAS  Google Scholar 

  38. Valenti F, Fausti F, Biagioni F, Shay T, Fontemaggi G, Domany E, et al. Mutant p53 oncogenic functions are sustained by Plk2 kinase through an autoregulatory feedback loop. Cell Cycle. 2011;10:4330–40.

    Article  CAS  Google Scholar 

  39. te Raa GD, Malcikova J, Pospisilova S, Trbusek M, Mraz M, Garff-Tavernier ML, et al. Overview of available p53 function tests in relation to TP53 and ATM gene alterations and chemoresistance in chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54:1849–53.

    Article  Google Scholar 

  40. Weller M. Predicting response to cancer chemotherapy: the role of p53. Cell Tissue Res. 1998;292:435–45.

    Article  CAS  Google Scholar 

  41. de Viron E, Knoops L, Connerotte T, Smal C, Michaux L, Saussoy P, et al. Impaired up-regulation of polo-like kinase 2 in B-cell chronic lymphocytic leukaemia lymphocytes resistant to fludarabine and 2-chlorodeoxyadenosine: a potential marker of defective damage response. Br J Haematol. 2009;147:641–52.

    Article  Google Scholar 

  42. Zupkovitz G, Grausenburger R, Brunmeir R, Senese S, Tischler J, Jurkin J, et al. The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation. Mol Cell Biol. 2010;30:1171–81.

    Article  CAS  Google Scholar 

  43. Richon VM, Sandhoff TW, Rifkind RA, Marks PA. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA. 2000;97:10014–9.

    Article  CAS  Google Scholar 

  44. Prochazka KT, Pregartner G, Rucker FG, Heitzer E, Pabst G, Wolfler A, et al. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Haematologica. 2019;104:516–23.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Xutao Guo for excellent technical support and thoughtful discussions. We thank Suming Huang for the critical review of the manuscript. This research was supported by NIH/NHLBI grant HL144712 to YQ.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA

    Bowen Yan, Qinwei Chen & Yi Qiu

  2. Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, 361003, China

    Qinwei Chen & Bing Xu

  3. Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Jianfeng Xu

  4. Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA, 92697, USA

    Jianfeng Xu & Wei Li

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Yan, B., Chen, Q., Xu, J. et al. Low-frequency TP53 hotspot mutation contributes to chemoresistance through clonal expansion in acute myeloid leukemia. Leukemia 34, 1816–1827 (2020). https://doi.org/10.1038/s41375-020-0710-7

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