11 Dec Abnormalities of PPM1D in Myeloproliferative Neoplasms
MedicalResearch.com Interview with:
Bridget Marcellino, MD
Icahn School of Medicine at Mount Sinai
Mount Sinai Hospital
MedicalResearch.com: What is the background for this study?
Response: Our work focuses on elucidating the mechanisms that drive the pathogenesis and progression of myeloproliferative neoplasms (MPN). Dysregulation of the TP53 pathway is associated with MPN progression evidenced by the association of TP53 loss of heterozygosity with transformation to acute myeloid leukemia (AML) and the presence of inactivating mutations of TP53 found in a proportion of MPN-related AML patients. Studies have shown that TP53 mutations, TP53 deletions and overexpression of the negative regulator of TP53, Murine Double Minute 2 (MDM2) all contribute to TP53 downregulation in MPNs and we therefore are interested in exploring other potential means by which TP53 is downregulated. Protein Phosphatase, Mg2+/Mn2+
Dependent 1D (PPM1D) is another negative regulator of the TP53 pathway and activating mutations in this gene are present in myeloid malignancies including MPNS. We therefore hypothesized that genomic alterations in PPM1D and/or overexpression of PPM1D would be found in the hematopoietic cells of MPN patients.
MedicalResearch.com: What are the main findings?
Response: We analyzed genomic data of 224 patients in clinical trials performed by the MPN-Research Consortium and found that 5/89 (5.6%) MPN patients who had transformed to AML and 4/135 (3.0%) high risk PV and essential thrombocythemia (ET) patients harbored at least 1 PPM1D mutation. All were truncating mutations, consistent with previous reports of PPM1D mutations in hematologic malignancies. Additionally, we identified 16/1,124 (1.4%) MPN patients in our cytogenetics database that had abnormalities involving the region of chromosome 17q that contains the PPM1D gene with 44% of these patients having MPN that transformed to AML.
Finally, we determined that a proportion of MPN patients without PPM1D mutations have overexpression of PPM1D transcript. PPM1D transcript levels were quantitated in mononuclear cells of MPN patients and compared to transcript levels from MNCs of healthy controls. Of the 31 patient specimens tested 42% had overexpression of PPM1D (1.5-8.0 fold increase). PPM1D overexpression was present in the following patient subsets 4/7 PV, 1/6 ET, 8/14 MF, 0/4 MPN-BP patients.
MedicalResearch.com: What should readers take away from your report?
Response: This study shows that abnormalities of PPM1D including activating mutations, cytogenetic aberrations and transcript overexpression are present in a significant proportion of MPN patients.
These early findings suggest that PPM1D may contribute to TP53 pathway dysregulation in MPNs and thereby influence disease pathogenesis and progression. PPM1D could therefore be a potential therapeutic target in this population.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We are currently corroborating these results in a larger cohort of MPN patients and additionally are delineating how these abnormalities influence the TP53 pathway. PPM1D inhibitors are currently under investigation is other malignancies and could hold potential for the treatment of MPNs. We are currently exploring the action of these agents in preclinical MPN models.
I have no disclosures to report.
Citation: Paper presented at ASH 2019
Result Type: Paper
Presenter: Bridget Marcellino
Program: Oral and Poster Abstracts
Session: 635. Myeloproliferative Syndromes: Basic Science: Poster III
Time and Location:
Monday, December 9, 2019: 6:00 PM-8:00 PM
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