Citations 2
Spectrum, prevalence, and clinical correlates of PPM1D mutations in patients with clonal hematopoiesis and clonal cytopenias
Badar, Talha , Marando, Ludovica , Latorre-Crespo, Eric, Oliva, Francyess Denis, Lin, Chenyu , McCormick, Benjamin J. , Kettani, Mobachir El , Shah, Kashish, Kusne, Yael , Jamy, Omer , Diebold, Kendall , Coltoff, Alexander , Finke, Christy M. , Foran, James M. , Kharfan‐Dabaja, Mohamed A. , Fan, Yao‐Shan, Jiang, Liuyan , He, Rong , Thomas, M. , Patel, Anand , Viswanatha, D., Shah, Maleeha, Mangaonkar, Abhishek A. , Kirschner, Kristina , Al‐Kali, Aref , Gangat, Naseema, Litzow, Mark R. , Patnaik, Mrinal M. , Latorre‐Crespo, Eric , Latorre, Eric , Lin, Chenyu , El Kettani, Mobachir , Kusne, Yael N , Jamy, Omer , Kharfan-Dabaja, Mohamed A , He, Rong , Patel, Anand , Viswanatha, David, Shah, Mithun V , Saliba, Antoine N , Kirschner, Kristina , Al-Kali, Aref , Gangat, Naseema , Litzow, Mark R. , Patnaik, Mrinal , Badar, Talha , Lasho, Terra L. , Thomas, Miles, Saliba, Antoine N. , Gangat, Naseema
Blood Advances | January 7, 2026 | Volume: 10 | Issue: 5 | Pages: 1746-1755
10.1182/bloodadvances.2025018031
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.
Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, fitness, and clonal structure
Latorre‐Crespo, Eric , Robertson, Neil , Kosebent, E. Gozde, Uddin, Md Mesbah , Honigberg, Michael C. , Bick, Alex, Reiner, Alexander P., Fiorillo, Edoardo , Chandra, Tamir , Kirschner, Kristina , Chandra, Tamir , Robertson, Neil A , Uddin, Md M , Honigberg, Michael C , Harris, Sarah , Schumacher, Linus , Chandra, Tamir , Kirschner, Kristina , Latorre, Eric , MacGillivray, Louise , Murphy, Lee , Whitsel, Eric A , Orrù, Valeria , Marongiu, Michele , Cucca, Francesco , Deary, Ian J. , Cox, Simon R. , Marioni, Riccardo E.
No container title available | March 3, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713, observations=2,341). We demonstrate pathway-specific fitness advantage and clonal composition influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual’s lifetime. We introduce MACS120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies.