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Project

Role of -1 programmed ribosomal frameshifting dysregulation on the JAK2 oncogene

The Janus Activated Kinase 2 (JAK2) V617F mutation constitutively activates JAK2 kinase activity and downstream JAK-STAT signaling in the majority of myeloproliferative diseases (MPD). Whereas this effect has been ascribed to the V617F amino acid change in the JAK2 protein, preliminary data from the host lab support that an additional regulatory mechanism at mRNA level called -1 programmed ribosomal frameshifting (-1 PRF) contributes to the strong transforming capacity of this mutation. More specifically, the nucleotide change encoding V617F is predicted to disrupt the secondary mRNA structure of the -1 PRF signal, leading to an increase of mutant JAK2 V617F mRNA and protein expression. Although well-characterized in viruses, little is known about -1 PRF in human cells. This project will be the first to thoroughly characterize the JAK2 -1 PRF signal and its unexplored impact in human disease. To this end, distinct nucleotide mutations will be introduced at the endogenous JAK2 locus in a human myeloid cell line via CRISPRCas9. Subsequent experiments will be conducted - some of which in an international collaboration with the lab of Prof. J. Dinman (University of Maryland, USA) - to investigate the effect of the PRF signal mutations on the mRNA structure, protein product and functional implications. Finally, we will explore modulating PRF activity as a novel therapeutic avenue to enhance currently inefficient JAK2 kinase activity inhibitor treatment for MPD.

Date:25 Jul 2020 →  Today
Keywords:-1 ribosomal frameshifting, myeloproliferative diseases, acute myeloid leukemia, Janus Kinase 2
Disciplines:Transcription and translation, Cancer biology
Project type:PhD project