Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias
Year: 2026
Type: article
Study design: Observational Study
Abstract: ABSTRACT: 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.
Source: Blood Advances
Authors: Talha Badar, Ludovica Marando, Eric Latorre, Terra Lasho, Francyess Denis Olivia, Chenyu Lin, Benjamin J. McCormick, Mobachir El Kettani, Kashish J. Shah, Yael Kusne, Omer Jamy, Kendall Diebold, Alexander Coltoff, Christy Finke, James Foran, Mohamed Kharfan-Dabaja, Yao-Shan Fan, Liuyan Jiang, Rong He, Miles Thomas, Anand Patel, David Viswanatha, Mithun Vinod Shah, Antoine Saliba, Abhishek Mangaonkar, Kristina Kirschner, Aref Al-Kali, Naseema Gangat, Mark Litzow, Mrinal M. Patnaik
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7118608735