PPM1D in Solid and Hematologic Malignancies: Friend and Foe?

Authors

Linda Zhang
Joanne I Hsu
Margaret A Goodell

Publication Date

9-2-2022

Journal

Molecular Cancer Research

DOI

10.1158/1541-7786.MCR-21-1018

PMID

35657598

PMCID

PMC9437564

PubMedCentral® Posted Date

6-3-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Cell Cycle Checkpoints, DNA Repair, Hematologic Neoplasms, Hematopoietic Stem Cells, Humans, Mutation, Protein Phosphatase 2C

Abstract

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 overexpression 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.