טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentKhier Yasmine
SubjectThe Role of Grb2 in Survival of Progenitors, HSC and
Leukemia Cells
DepartmentDepartment of Medicine
Supervisors Dr. Yishai Ofran
Dr. Igal Louria-Hayon
Full Thesis textFull thesis text - English Version


Abstract

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.