Spectrum, prevalence, and clinical correlates of <i>PPM1D</i> mutations in patients with clonal hematopoiesis and clonal cytopenias
TP53 and PPM1D are key regulators of DNA damage response and repair, and somatic mutations in these genes often co-occur in hematopoietic cells, expanding under genotoxic stress. Unlike TP53 mutations, where mechanisms of progression are defined, pathways underlying clonal fitness and transformation in PPM1D mutant cells remain unclear. In collaboration with 5 academic institutions, we analyzed the clinical and molecular landscape of 337 patients with clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across 4 genotypes: PPM1Dmt/TP53wt (n = 170 [50%]), PPM1Dmt/TP53mt (n = 25 [7%]), TP53mt/PPM1Dwt (n = 17 [5%]), and TP53wt/PPM1Dwt (n = 125 [38%]). All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (range, 0.3%-64%). The PPM1Dmt/TP53mt genotype was most frequently encountered in therapy-related CH/CCUS (t-CH/t-CCUS; 80%, 66.5%, 76.5%, and 19%; P ≤ .001) and had a shorter time interval to detection from last genotoxic exposure (6.2, 5.9, 11.25, and 24.5 months; P ≤ .001) compared with PPM1Dmt/TP53wt, TP53mt/PPM1Dwt, and TP53wt/PPM1Dwt genotypes, respectively. Acknowledging the short follow-up duration, rates of malignant transformation were lower in the PPM1Dmt/TP53wt (2%) and PPM1Dmt/TP53mt (4%) groups compared with PPM1Dwt/TP53wt (12%) and PPM1Dwt/TP53mt (17%) groups (P ≤ .001), respectively. In summary, PPM1D mutations are frequently observed in t-CH/t-CCUS, with low median VAFs, and are associated with low rates of progression, even when comutated with TP53.
Authors
- D. Viswanatha
- Antoine N. Saliba (ORCID: https://orcid.org/0000-0001-5134-7336)
- Terra L. Lasho (ORCID: https://orcid.org/0000-0002-0315-5230)
- Aref Al‐Kali (ORCID: https://orcid.org/0000-0002-0824-3715)
- Abhishek Avinash Mangaonkar (ORCID: https://orcid.org/0000-0003-2458-9887)
- Yao Fan (ORCID: https://orcid.org/0000-0002-8795-9059)
- Mohamed A. Kharfan‐Dabaja (ORCID: https://orcid.org/0000-0001-7394-5185)
- Francyess Denis Oliva
- Ludovica Marando (ORCID: https://orcid.org/0000-0002-6154-850X)
- Omer Jamy (ORCID: https://orcid.org/0000-0003-2411-4742)
- James M. Foran (ORCID: https://orcid.org/0000-0003-1673-1708)
- Anand Patel (ORCID: https://orcid.org/0000-0002-0296-8686)
- Kendall Diebold
- Cheng-Yu Lin
- Liuyan Jiang (ORCID: https://orcid.org/0000-0002-9851-985X)
- Maleeha Shah
- Yael N. Kusne (ORCID: https://orcid.org/0000-0002-7325-8454)
- Mrinal M. Patnaik (ORCID: https://orcid.org/0000-0001-6998-662X)
- Alexander Coltoff
- Christy M. Finke (ORCID: https://orcid.org/0009-0006-2843-9025)
- Talha Badar (ORCID: https://orcid.org/0000-0003-1548-918X)
- Rong Lucy He (ORCID: https://orcid.org/0000-0001-6116-8163)
- Mark Robert Litzow (ORCID: https://orcid.org/0000-0002-9816-6302)
- Kashish Shah
- M. Thomas (ORCID: https://orcid.org/0000-0003-4381-965X)
- Mobachir El Kettani (ORCID: https://orcid.org/0009-0005-6354-072X)
- Eric Latorre-Crespo
- Naseema Gangat
- Kristina Kirschner
- Benjamin J. McCormick
Institutions
- Mayo Clinic (US)
- Medical University of South Carolina (US)
- Duke University (US)
- Jacksonville College (US)
- WinnMed (US)
- University of Alabama at Birmingham (US)
- University of Chicago (US)
- Centre de Recerca Matemàtica (ES)
- Mayo Clinic Hospital (US)
- Centre for Genomic Regulation (ES)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2026-01-07
- DOI
- https://doi.org/10.1182/bloodadvances.2025018031
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 35.41
Funders
- Amgen
- Pfizer
- Incyte
- Syndax Pharmaceuticals
- Servier
- Swedish Orphan Biovitrum
- MorphoSys
- Center for Individualized Medicine, Mayo Clinic
- Agencia Estatal de Investigación