Molecular Consequences and Targeting of PPM1D Overexpression in Myeloproliferative Neoplasms
Year: 2026
Type: article
Abstract: Phosphatase Mg2+/Mn2+ dependent 1D protein (PPM1D) is a serine threonine phosphatase known to regulate oncogenic pathways. PPM1D mutations are enriched in therapy-related MDS and AML, but the role of PPM1D in myeloproliferative neoplasms (MPN) remains largely unexplored. By sequencing 519 MPN patients, we detected activating PPM1D mutations in 3.1% of them. Importantly, PPM1D was overexpressed in hematopoietic stem and progenitor cells (HSPCs) in most PPM1D wild-type (WT) MPN cases. To elucidate the impact of PPM1D mutations on MPN HSPCs, we generated isogenic JAK2V617F+/PPM1D-WT and JAK2V617F+/PPM1D mutant (MUT) induced pluripotent stem cell (iPSC) lines from a MPN patient. Single-cell RNA-sequencing (scRNA-seq) of iPSC derived HSPCs revealed altered TP53, DNA damage response and cell cycle regulation. scRNA-seq analysis of primary PPM1D-MUT MPN patient mononuclear cells (MNCs) further confirmed upregulation of MYC, mTORC1, OXPHOS, JAK/STAT, and NF-κB pathways and corresponding genes in HSCs. The allosteric PPM1D inhibitor (PPM1Di) GSK2830371 preferentially inhibited colony formation in myelofibrosis (MF) samples. Combination treatment of GSK2830371 with low dose inhibition of HDM2, a negative regulator of p53, significantly improved targeting of JAK2V617F+ HSPCs, while sparing normal HSPCs. Single-cell mutational and protein analysis of a clonally complex MF patient sample treated with this combination strategy revealed reduced mutated clones and increased WT clones by >4-fold. Dual PPM1D and HDM2 targeting also significantly decreased leukemic burden in a xenograft MPN model. These findings support PPM1D as a critical MPN HSPCs regulator and support dual PPM1D/HDM2 inhibition as a treatment strategy for MF patients.
Source: Blood
Authors: Md. Babu Mia, Christoph Schaniel, Cara Clementelli, Sarah Elisabeth Haines, Malgorzata Olszewska, JoAnn Arandela, Sebastian Elghaity-Beckley, Sophie Klingborg, Zinedine Hoque, Ayman Mohammad, Shwetha Hara Sridhar, Brianna Kelly, Xiaoli Wang, Emmanuel Olivier, Alan H Shih, Blake T. Langlais, Allison Cote, Noushin Farnoud, Raajit K. Rampal, Duke Butterfield, Amylou C. Dueck, Min Lu, Kristin G Beaumont, Robert Sebra, John O. Mascarenhas, Eirini P Papapetrou, Ronald Hoffman, Bridget K Marcellino
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
Funder: National Cancer Institute
OpenAlex ID: W7221715380
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