Related Experiment Video
Updated: Sep 21, 2025
Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up
Published on: March 26, 2018
PPM1D in Solid and Hematologic Malignancies: Friend and Foe?
Linda Zhang1,2, Joanne I Hsu1,2, Margaret A Goodell2,3
1Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, Texas.
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.
Insights
Protein phosphatase PPM1D regulates DNA damage response and is implicated in cancer. Mutations in PPM1D are frequent in clonal hematopoiesis and may drive leukemic transformation, impacting treatment strategies.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The DNA damage response (DDR) is crucial for maintaining genome stability, and its failure is a hallmark of cancer.
- Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) is a key negative regulator of the DDR, frequently altered in solid tumors.
- PPM1D alterations correlate with aggressive cancer phenotypes and poor patient prognosis in solid malignancies.
Purpose of the Study:
- To investigate the role of PPM1D in hematologic malignancies, particularly in the context of clonal hematopoiesis (CH).
- To elucidate the mechanisms by which PPM1D mutations or overexpression contribute to cancer development.
- To explore the differential roles of PPM1D in solid versus hematologic oncogenesis and identify potential therapeutic targets.
Main Methods:
- Review of recent findings on PPM1D function in DNA damage response.
- Analysis of large-scale genomic studies identifying PPM1D mutations in CH.
- Examination of mechanisms including suppression of DNA repair, cell-cycle arrest, and apoptosis.
Main Results:
- PPM1D is frequently mutated in individuals with CH, an age-associated phenomenon.
- PPM1D mutations are enriched in therapy-related myeloid neoplasms, suggesting a role in leukemic transformation.
- PPM1D alterations can impair DNA repair, cell-cycle arrest, and apoptosis, promoting malignancy.
Conclusions:
- PPM1D plays a significant role in both solid and hematologic cancers.
- Understanding PPM1D's function in CH and leukemogenesis is critical for developing new therapies.
- Targeting PPM1D may offer novel therapeutic avenues for various malignancies.
