The role of NCK1 in CSF3R-driven myeloproliferative neoplasms

点击翻译按钮获取中文摘要

PROJECT SUMMARY Colony Stimulating Factor 3 Receptor (CSF3R) is the primary receptor that drives the production of mature neutrophils, activating signaling pathways to control proliferative and differentiation transcriptional programs. CSF3R is recurrently mutated in poor-prognosis myeloproliferative neoplasms (MPNs). These mutations activate CSF3R to enhance signaling through the JAK/STAT and MAPK pathways, resulting in an overproduction of neutrophils. Drug development efforts have been focused on targeting the JAK/STAT activation. However, recent studies have shown that enhanced MAPK pathway signaling may be equally important in disease pathobiology. The precise mechanisms by which CSF3R activates the MAPK pathway are not fully understood. Identifying novel players linking CSF3R to MAPK signaling would offer new therapeutic targets to explore, and allow for a greater understanding of CSF3R signaling in normal and aberrant hematology. Using a protein-protein interaction screen, I identified several CSF3R interacting partners that are known to modulate MAPK pathway activation, including the signaling adapter NCK1. My preliminary data shows that NCK1 plays critical role in activation of the MAPK pathway and is required in CSF3RT618I-driven proliferation. I hypothesize that NCK1 is an essential regulator of CSF3R-driven MAPK pathway activation and myeloid proliferation. In Aim 1, I will map the essential regions and residues of CSF3R that are necessary for NCK1 to potentiate MAPK activation, and establish a role for NCK1 in the control of myeloproliferative transcriptional programs. In Aim 2 I will investigate how NCK1 controls myeloid differentiation, and determine whether NCK1 expression is required for the biogenesis of CSF3RT618I-driven myeloproliferative neoplasms in vivo. These experiments will uncover the role of NCK1 in CSF3R-driven MAPK pathway activation and its role in normal and aberrant hematopoiesis. This fellowship will prepare me for the next stage in my academic career by providing me with new skills working with in vivo models and transcriptomics, strengthening my understanding of hematologic disease, and supporting my professional development. During the NRSA fellowship I will be mentored by Dr. Julia Maxson and Dr. Jeffrey Tyner, who are exceptional advisors and well poised to support my growth and project development.