PPM1D mutations appear in complete remission after exposure to chemotherapy without predicting emerging AML relapse

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Evolution of PPM1D and co-occuring mutations during treatment in AML patients with relapse.
Fig. 2: Evolution of PPM1D and co-occuring mutations during treatment in AML patients without relapse.


  1. 1.

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

    Article  Google Scholar 

  2. 2.

    Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  Google Scholar 

  3. 3.

    Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012;150:264–78.

    CAS  Article  Google Scholar 

  4. 4.

    Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477–87.

    Article  Google Scholar 

  5. 5.

    Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488–98.

    Article  Google Scholar 

  6. 6.

    Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20:1472–8.

    CAS  Article  Google Scholar 

  7. 7.

    Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35–47.

    CAS  Article  Google Scholar 

  8. 8.

    Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21:374–82.

    CAS  Article  Google Scholar 

  9. 9.

    Gibson CJ, Lindsley RC, Tchekmedyian V, Mar BG, Shi J, Jaiswal S, et al. Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol. 2017;35:1598–605.

    CAS  Article  Google Scholar 

  10. 10.

    Wong TN, Miller CA, Jotte MRM, Bagegni N, Baty JD, Schmidt AP, et al. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun. 2018;9:455.

    Article  Google Scholar 

  11. 11.

    Chuman Y, Kurihashi W, Mizukami Y, Nashimoto T, Yagi H, Sakaguchi K. PPM1D430, a novel alternative splicing variant of the human PPM1D, can dephosphorylate p53 and exhibits specific tissue expression. J Biochem. 2009;145:1–12.

    CAS  Article  Google Scholar 

  12. 12.

    Lu XB, Nguyen TA, Moon SH, Darlington Y, Sommer M, Donehower LA. The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metast Rev. 2008;27:123–35.

    Article  Google Scholar 

  13. 13.

    Fiscella M, Zhang HL, Fan SJ, Sakaguchi K, Shen SF, Mercer WE, et al. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. PNAS. 1997;94:6048–53.

    CAS  Article  Google Scholar 

  14. 14.

    Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 2013;493:406–10.

    CAS  Article  Google Scholar 

  15. 15.

    Hsu JI, Dayaram T, Tovy A, De Braekeleer E, Jeong M, Wang F, et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell. 2018;23:700–13.

    CAS  Article  Google Scholar 

  16. 16.

    Kahn JD, Miller PG, Silver AJ, Sellar RS, Bhatt S, Gibson C, et al. PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood. 2018;132:1095–105.

    CAS  Article  Google Scholar 

  17. 17.

    Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    CAS  Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Peter J. M. Valk.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Al Hinai, A.S.A., Grob, T., Rijken, M. et al. PPM1D mutations appear in complete remission after exposure to chemotherapy without predicting emerging AML relapse. Leukemia (2021).

Download citation


Quick links