CBL and the Negative Regulation of Cytokine Receptor Signaling

Abstract

Cytokines play an essential role in the growth, differentiation, and effector functions of hematopoietic cells. The control of cytokine-mediated signaling is critical to maintaining both cellular- and organismal-level homeostasis, and many human diseases arise from aberrant cytokine signaling. Identifying and characterizing the mechanisms controlling the strength and kinetics of cytokine receptor signaling are essential to our understanding of the pathogenic mechanisms of disease and to the development of therapies for diseases arising from aberrant signaling. CBL is an E3 ubiquitin ligase and signaling scaffold that both positively and negatively regulates tyrosine kinase signaling. Recently, mutations have been identified in a number of myeloid malignancies, including chronic myelomonocytic leukemia. This thesis examines the role of CBL, an E3 ubiquitin ligase, in cytokine receptor signaling, describes mechanisms by which mutations in CBL give rise to myeloid malignancies, and identifies possible therapeutic targets. In the introduction, we review our current knowledge of CBL, chronic myelomonocytic leukemia, and IL-3/IL-5/GM- CSF signaling. In the second chapter, we use proteomic and phospho-proteomic techniques to reveal the hyperactivation of a LYN-CBL-PI3K axis in CBL mutant cells and demonstrate the efficacy of a LYN inhibitor, dasatinib, in CBL-mutant patient- derived xenograft mouse models. In the third chapter, we use CRISPR genetic screens to identify genes required for the differential growth of CBL WT and CBL-mutant cells and uncover a compensatory relationship between CBL and CUL5 in the negative regulation of STAT5 signaling. In the fourth chapter, we use a genetic screen and analysis of the Cancer Dependency Map to reveal a mechanism of CSF2RB regulation by a STUB1/CHIC2 complex. Together, these findings provide insight into the normal mechanisms of cytokine receptor regulation, the oncogenic mechanisms of diseases arising from aberrant cytokine signaling, and novel therapeutic opportunities for patients suffering from fatal malignancies.