Skip to main content

Elucidation of DNA Damage Response mechanisms in human normal and leukemia stem cells

Final Report Summary - HSCSPECDDR (Elucidation of DNA Damage Response mechanisms in human normal and leukemia stem cells)

Life-long blood regeneration is critically dependent on self-renewing multipotential hematopoietic stem cells (HSCs). HSCs’ nearly unlimited self-renewal potential and lifetime persistence in the body, in contrast to the committed progenitors (CP), signifies the need for HSCs genome integrity tight control. Indeed, accumulation of unrepaired DNA damage in HSCs is associated with bone marrow failure and accelerated leukemogenesis. Yet, the molecular basis and physiological significance of these HSC-specific DDR characteristics remain unexplored. To bridge the gap in this highly significant knowledge I and my research group during the period of CIG grant (2013-2017) pursued high resolution analysis of DDR signalling in the highly purified HSC and CP subsets isolated from physiologically distinct developmental stages of human hematopoiesis. Furthermore, we achieved a milestone in the identification and characterization of several functional regulators engaged by genotoxic stress in normal and leukemia stem cells. This original study will form the foundation for my long-term goals of identifying regulators of DDR in human HSCs and in leukemia initiating cells, revealing mechanisms utilized by self-renewing cells to maintain genome integrity and combat stress, and provide novel insights into leukemogenesis, blood regeneration and aging CIG funds had an important positive impact on the several aspects of my career as a new tenure track faculty at the Department of Pathology. Firstly, I was able to hire high quality students and research associates. Secondly, the career award allowed me financial freedom to explore different research directions outlined in my plan in a parallel fashion. Thirdly, this grant freed my time to mentor closely my students and even run some experiments together – the most exciting part of science. Importantly, I was able to use some funds for participation in conferences and to support student exchange – a highly efficient way to establish vital collaborations and gain scientific recognition. The four-year CIG funding helped me tremendously to accomplish my research objectives and yielded several publications (Biechonski et al, Int J Cancer 2017, Zipin-Roitman et al, Oncotarget 2017). The CIG assisted me also in securing more funds from additional sources. Therefore, the career integration grant indeed greatly benefit my career in terms of achieving university tenure, which will provide me with long-term job stability and is another step towards my ultimate career goal – being a full professor at Tel Aviv University.
Collectively, Marie Curie funding gives my laboratory a head start toward achieving milestones in our understanding of the DDR in normal and malignant hematopoiesis. On this foundation, I will strive to build a centre of excellence in stem cell research in Europe.