PPM1D in Solid and Hematologic Malignancies: Friend and Foe?

In the face of constant genomic insults, the DNA damage response (DDR) is initiated to preserve genome integrity; its disruption is a classic hallmark of cancer. Protein phosphatase Mg2+ /Mn2+ -dependent 1D (PPM1D) is a central negative regulator of the DDR that is mutated or amplified in many solid cancers. PPM1D overexpression is associated with increased proliferative and metastatic behavior in multiple solid tumor types and patients with PPM1D-mutated malignancies have poorer prognoses. Recent findings have sparked an interest in the role of PPM1D in hematologic malignancies. Acquired somatic mutations may provide hematopoietic stem cells with a competitive advantage, leading to a substantial proportion of mutant progeny in the peripheral blood, an age-associated phenomenon termed clonal hematopoiesis (CH). Recent large-scale genomic studies have identified PPM1D to be among the most frequently mutated genes found in individuals with CH. While PPM1D mutations are particularly enriched in patients with therapy-related myeloid neoplasms, their role in driving leukemic transformation remains uncertain. Here, we examine the mechanisms through which PPM1D over -expression or mutation may drive malignancy by suppression of DNA repair, cell-cycle arrest, and apoptosis. We also discuss the divergent roles of PPM1D in the oncogenesis of solid versus hematologic cancers with a view to clinical implications and new therapeutic avenues.

Automated summary

PPM1D, a central negative regulator of DNA damage response, is mutated or amplified in many solid cancers and associated with increased proliferative and metastatic behavior. Recent findings have sparked interest in PPM1D's role in hematologic malignancies, with its mutations being commonly found in clonal hematopoiesis. Further research is needed to understand the divergent roles of PPM1D in solid vs hematologic cancers and its potential implications for new therapeutic avenues.