|M.Sc Student||Khier Yasmine|
|Subject||The Role of Grb2 in Survival of Progenitors, HSC and|
|Department||Department of Medicine||Supervisors||Dr. Yishai Ofran|
|Dr. Igal Louria-Hayon|
|Full Thesis text|
Although HSC proliferation, survival and expansion have been shown to be supported by the cooperative action of different cytokines and molecules, slightly is known about the intracellular signaling pathways controlling the regulation of HSC. Growth factor receptor bound protein 2 (Grb2) is a ubiquitous adaptor protein known to be involved in signaling induced by a variety of growth factors and cytokines; however, its physiological role in HSC has never been characterized yet. Our study has shown that Grb2 mRNAs are highly expressed in HSC relative to more differentiated cells of the myeloid and erythroid lineages. Conditional deletion of Grb2 induced a decline of long-term (LT-) HSC numbers. Moreover, it diminished HSC regenerative and self-renewing abilities in a cell-autonomous fashion. We have revealed that Grb2 deletion not only impaired HSC proliferative response to 5-FU treatment in vivo, but also affects the survival of HSC. Besides, this study has shown that competitive inhibition of Grb2 in AML cells impairs their survival.
Our findings position Grb2 as a key adaptor, positive regulator protein of LT-HSC
transplantation, proliferation and survival. In addition, we recommend further
investigations of Grb2 protein in LSCs as a potential therapeutic target of AML.