CoChat
Sign Up
Cited by 427Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationProtein Tyrosine Phosphatases

PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy

Open access
Hsu, Joanne I., Dayaram, Tajhal, Tovy, Ayala, De Braekeleer, Etienne, Jeong, Mira, Wang, Feng, Zhang, Jianhua, Heffernan, Timothy P. +12 more·2018·Cell stem cell
DOI 10.1016/j.stem.2018.10.004PMC PMC6224657
Open this paper in CoChat — free accountOpen PDF

Abstract

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn 2+ /Mg 2+ -dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. Video Abstract

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.stem.2018.10.004

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Ppm1d loss confers an advantage only in the context of the selective environment of cytotoxic chemotherapy or radiation, but not in steady-state post-transplant conditions.

    “Ppm1d loss confers an advantage only in the context of the selective environment of cytotoxic chemotherapy or radiation, but not in steady-state post-transplant conditions [53,54].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [54]

    The Results sections on cisplatin exposure and transplantation report that Ppm1d R451X mutant cells gained an advantage with cisplatin but did not expand after transplantation without chemotherapy (page unavailable in our copy). The claim substitutes Ppm1d loss for that mutation: the paper explicitly distinguishes loss in knockout mice from hyperactivity in the mutations it studied. It also does not establish a selective advantage under radiation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • HSCs from mice with mutations in both Tp53 and Ppm1d are able to enter cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.

    “HSCs from mice with mutations in both Tp53 42 and Ppm1d, a gene encoding a regulator of p53 and other members of the DNA damage response pathway, 43,44 are able to enter cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.”

    From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [44]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

2 of the 49 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Hsu, J. I., Dayaram, T., Tovy, A., De Braekeleer, E., Jeong, M., Wang, F., Zhang, J., Heffernan, T. P., Gera, S., Kovacs, J. J., Marszalek, J. R., Bristow, C., Yan, Y., Garcia-Manero, G., Kantarjian, H., Vassiliou, G., Futreal, P. A., Donehower, L. A., Takahashi, K., & Goodell, M. A.
Affiliations
  • Baylor College of Medicine (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Texas Health Science Center at Houston (US)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
Corresponding author
  • Takahashi, Koichi
  • Goodell, Margaret A.
ORCID
Venue
Cell stem cell
Publisher
Elsevier BV
Published
2018-11
Volume
23
Issue
5
Pages
700-713.e6
ISSN
  • 1875-9777 (ISSN-L)
  • 1934-5909
DOI
10.1016/j.stem.2018.10.004
PMC
PMC6224657
OpenAlex
W2899272142
Cited by
425
References
49
Citations by year
2026: 40 · 2025: 54 · 2024: 64 · 2023: 67 · 2022: 62 · 2021: 47 · 2020: 54 · 2019: 35 · 2018: 1
FWCI
24.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell stem cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Center Prevention and Research Institute of Texas (RP160451, R120501)
  • NIH (DK092883, DK116428, S10RR024574, AI036211, P30 CA125123, P30 CA016672)
  • The Welch Foundation (G-0040)
  • MD Anderson’s MoonShot Program
  • Baylor Research Advocates for Student Scientists
  • BCM MSTP program
  • Khalifa Physician Scientist Award
  • Physician Scientist Program at MD Anderson
  • Leukemia SPORE Career Enhancement Award
  • Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015)
  • Kay Kendall Leukaemia Fund
  • Bloodwise
  • Sanger Institute (WT098051)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
clonal hematopoiesis, PPM1D mutation, protein phosphatase 2A, cisplatin, therapy-related acute myeloid leukemia, myelodysplastic syndrome, DNA damage response, apoptosis resistance, doxorubicin, bone marrow transplantation, hematopoietic stem cells
MeSH terms
Protein Phosphatase 2C, Aged, Animals, Antineoplastic Agents, Cisplatin, Clone Cells, Doxorubicin, Drug Screening Assays, Antitumor, Female, Hematopoiesis, Humans, Male, Mice, Inbred C57BL, Middle Aged, Mutation, Neoplasms, Experimental, Leukemia, Myeloid, Acute, Mice, Inbred NOD, Cell Proliferation, Mice, HEK293 Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review