Project Details
Projekt
Identification and targeting of mutated PPM1D for preventing cardiovascular events and therapy-related myeloid neoplasms in cancer survivors (project A5)
Applicant
Dr. Anjali Cremer
Subject Area
Hematology, Oncology
Cardiology, Angiology
Cardiology, Angiology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962
Clonal hematopoiesis (CH) can result from mutations in genes involved in the DNA damage response (DDR) pathway, such as Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D). PPM1D mutations lead to a loss of a C-terminal degradation motif resulting in its accumulation. Longitudinal sequencing studies reported that mutations in PPM1D and TP53 were more prevalent in cancer survivors who were previously treated with cytotoxic therapy, than in untreated patients. This patient cohort also has an increased risk to develop therapy related myeloid neoplasms (tMN), as well as heart failure with a poor outcome. The role of PPM1D mutations in the development of these diseases is incompletely understood. Here, we will elucidate by integration of CRISPR-Cas9 screenings, MS-based quantitative proteomics, as well as in vivo mouse models the underlying mechanisms how PPM1D mutations under cytotoxic stress lead to observed diseases and will identify new targeted treatment strategies. We will achieve these aims by i) characterizing the interactome of mutant PPM1D vs. wildtype PPM1D, ii) understanding the dynamics between TP53 clones and PPM1D clones, giving us an answer whether PPM1D is acting via p53-independent mechanisms under stress. Additionally, we will iii) identify genes that are essential for PPM1D protein stability and potentially find drugs, which can be repurposed to target PPM1D clones. Lastly, we will iv) delineate the contributing role of PPM1D in promoting inflammation, eventually leading to increased cardiac damage in patients who underwent cytotoxic therapies. In summary, this project will shed light on the various altered signaling pathways, in which mutated PPM1D is involved and inform us about new targeted treatment strategies for patients harboring PPM1D CH with the goal to prevent cardiac dysfunction as well as tMN in a particularly vulnerable patient cohort.
DFG Programme
Research Units
