Project Details
Projekt
Targeting aberrant cell signaling to eradicate persistent MPN cells
Applicant
Ashok Kumar Jayavelu, Ph.D.
Subject Area
Hematology, Oncology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 517204983
Myeloproliferative neoplasms (MPNs) represent chronic clonal disorders characterized by an overproduction of mature hematopoietic cells. This group includes three distinct clinical entities: polycythemia vera, myelofibrosis and essential thrombocythemia. The genomic characterization of MPN patients identified mutations in Janus kinase 2 (JAK2), Calreticulin (CALR) and Thrombopoietin receptor (MPL) as disease drivers. Significant advancements in the understanding of disease biology, identifying co-operating genetic mutations, exploration of functional consequences of disease drivers, mechanism of disease and development of jak kinase inhibitors now ultimately offers the potential for diagnosis, risk stratification and treatment. Nonetheless, our understating of MPNs is continuously evolving. The integration of proteogenomic traits could provide new perspective, functional signaling aspects might unveil non-genetic processes involved in driving the disease. In clinical practice, administered of Jak inhibitor (Ruxolitinib) to MPN patient demonstrated significant improvements in symptoms, quality of life, and overall survival thus offering an alternative to hydroxyurea or interferon-alpha treatments. Despite its efficacy, complete eradication of JAK2-mutated cells in patient by ruxolitinib is challenging due to the persistence of a clone of disease driving persistent cells. As a result, a deeper comprehension of the disease's underlying biology is imperative to pinpoint potential therapeutic targets for more effective interventions. To uncover the downstream effectors of the mutant Jak2 kinase that may be responsible for the persistence of MPN, we performed in-depth mass spectrometry (MS)-based phosphoproteome profiling on Jak2-mutated cells. The functional phosphoproteome approach uncovered phosphorylation of splicing factor in Jak2-mutated cells play a crictial role in mediating drug persistence. In this proposal, our objective is to broaden the scope of our investigation beyond the persistence landscape of Jak2-mutated cells and encompass all pertinent driver mutations in MPNs. By doing so, we seek to identify and compare the specific dependencies of Jak2, thrombopoietin receptor (Mpl)- and calreticulin (Calr)-mutated cells. Consequently, this work aims to identify and address distinct vulnerabilities prompted by these mutations in order to develop targeted therapeutic strategies.
DFG Programme
Research Units
