Dissecting the post-translational regulatory architecture of splicing factors in myeloid malignancies

• Applicant: Ashok Kumar Jayavelu, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467181161

mRNA splicing is a fundamental process that occurs in a eukaryotic cell. Splicing is dynamically regulated by a multi-megadalton protein-RNA complex called the spliceosome. Splicing factor genes frequently mutated in solid cancer and in hematological malignancies. Dys-regulation by altered transcript expression of core spliceosome components was also shown to play a role in tumor progression. However, the spliceosome is a macro molecular-dynamic complex that is spatio-temporally regulated. Importantly, the post-translational events that regulate the splicing factors represents an unexplored territory in cancer. Using a functional phosphoproteome profiling approach, we have previously discovered that oncokinase Jak2 promotes phosphorylation of splicing factors and is required upon Jak inhibitor exposure to mediate a disease persistence phenotype in myeloproliferative neoplasm. Interestingly, direct targeting of the phosphorylated splicing factor or its downstream effectors in combination with Jak-inhibition overcomes the disease persistence in Jak2 mutated neoplasms. Our work identified and validated novel cell-intrinsic mechanisms of differential splicing factor phosphorylation that result in splicing-dependent alterations of Jak2-ERK-signaling and maintenance of Jak2V617F malignant clones. How splicing factors as a class are post-translationally regulated by signaling pathways remains so far elusive, and this understanding may unravel novel mechanisms with translational relevance for therapeutic targeting. The aim of this project is to systematically investigate the regulators and pathways that mediate post-translational modifications, which control the function of splicing factors in myeloid malignancies. Thereby the mechanisms of splicing factor regulation that underly disease progression and drug response in myeloid malignancies will be elucidated. Ultimately, we aim to pave the way for the identification of novel therapeutic targets.

• DFG Programme: Independent Junior Research Groups