The role of the PPM1D gene in the carcinogenesis of myeloid neoplasms: molecular mechanisms and prospects for targeted therapy

Objective : to summarize the accumulated knowledge on the role of PPM1D phosphatase in clonal hematopoiesis and the pathogenesis of hematological malignancies, particularly in acute myeloid leukemia, as well as to evaluate the feasibility of therapeutic targeting of PPM1D using specific inhibitors. Materials and Methods . A search for relevant sources was conducted in the Web of Science, PubMed, and Scopus databases. Publications were selected based on the relevance of the studies and the pertinence of their subject matter to the topic of the review, the literature search was performed using the following key terms: “mutations of PPM1D ", “PPM1D and cancer”, “clonal hematopoiesis”, “PPM1D and clonal hematopoiesis”, “ PPM1D gene”, “WIP1 phosphatase”, “clonal hematopoiesis of indeterminate potential”, “therapy-related AML”, “p53 signaling pathway”, “cell cycle regulation”, “targeted cancer therapy”, “hematologic malignancies”, “truncating mutations” and “inhibitors of PPM1D”. A total of 142 sources were analyzed, of which 63 were included in the review. Results. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized as a condition involving somatic mutations in driver genes of myeloid neoplasms at a variant allele frequency of ≥2 % in blood cells of individuals without hematological disorders. The prevalence of CHIP exceeds 10 % in individuals over 60 years of age and reaches 25 % in cancer patients. Antineoplastic therapy promotes the selection of hematopoietic stem cell clones harboring mutations, including mutations in the PPM1D gene, which substantially increases the risk of developing therapy-related myeloid neoplasms (t-MN). PPM1D phosphatase is a negative regulator of p53 and numerous cell death pathways. Its overexpression is detected in various types of solid tumors (ovarian cancer, breast cancer, and others), while its mutations are identified in 1-2 % of patients with de novo myeloid neoplasms and in 10-20 % of patients with t-MN. Recent studies demonstrate the predominant role of PPM1D mutations in age-associated clonal hematopoiesis, in the context of telomere shortening, and in the presence of germline DNA repair mutations, thereby underscoring the pivotal significance of this phosphatase in the pathogenesis of myeloid disorders. Conclusion. PPM1D represents a promising therapeutic target for the treatment of AML owing to its key role in the regulation of multiple cell death pathways and the cellular stress response. PPM1D inhibitors may serve as a foundation for the development of combination therapy regimens, particularly for elderly patients and those with acquired resistance to antineoplastic agents.