Genetic roadmaps to synthetic lethality in myeloproliferative neoplasms (MPNs)
Tomasz SkorskiPhD, MD, DSc
Project Term: July 1, 2021 - June 30, 2024
Myeloproliferative neoplasms (MPNs) carry JAK2(V617F), MPL(W515L) and mutations in calreticulin (CALRmut) often accompanied by mutations in TET2, ASXL1, DNMT3A, EZH2, and other genes. We will develop a strategy based on gene mutation profiling to identify MPNs displaying specific defects in DNA repair. These defects will be then explored by specific DNA repair inhibitors to eliminate quiescent and proliferating MPN stem and progenitor cells without affecting normal cells and tissues.
Although tremendous progress has been made in treatment modalities of myeloproliferative neoplasms (MPNs), patients are prone to malignant progression. Thus, there is the necessity to improve and develop novel therapeutic approaches. MPNs usually express JAK2(V617), MPL(W515L), or calreticulin (CLTR) mutations, which may be accompanied by additional mutations in TET2, ASXL1, DNMT3A, EZH2, IDH1, and other genes. Therefore, MPNs represent truly complex disorders with mixed phenotype and genetic background, creating problems to find effective therapeutic approach. MPN cells accumulate spontaneous DNA damage. In addition, cytotoxic drugs causing potentially lethal DNA damage are often employed to treat MPNs. Thus, survival of MPN cells depends on DNA repair and DNA repair inhibitors may selectively induce MPN cell death. We propose to identify specific mutation sets [e.g., JAK2(V617F)+EZH2] causing specific DNA repair defects in individual MPN patients and to examine the mechanisms responsible for this effect. DNA repair deficiencies will be explored by DNA repair inhibitors (e.g. PARP inhibitors) combined with already approved drugs to eliminate quiescent and proliferating MPN stem and progenitor cells without affecting normal cells and tissues. This approach may lead to personalized treatment of MNPs.