Strategies for Genome Repair in Normal and Leukemic Stem Cells

Abstract SCI-41

Blood development is organized hierarchically, starting with a rare but well-defined population of hematopoietic stem cells (HSC) that give rise to a series of committed progenitors and mature cells with exclusive functional and immunophenotypic properties. HSC are the only cells within the hematopoietic system that self-renew for life, whereas other hematopoietic cells are short-lived and committed to the transient production of mature blood cells. Under steady-state conditions, HSC are a largely quiescent, slowly cycling cell population that, in response to environmental cues, is capable of dramatic expansion and contraction to ensure proper homeostatic replacement of all blood cells. While considerable work has deciphered the molecular networks controlling HSC activity, still little is known about how these mechanisms are integrated at the cellular level to ensure life-long maintenance of a functional HSC compartment. HSC reside in hypoxic niches in the bone marrow microenvironment, and are mostly kept quiescent in order to minimize stress and the potential for damage associated with cellular respiration and cell division. Recently, we have shown that HSC can also engage specialized response mechanisms that protect them from the killing effect of environmental stresses such as ionizing radiation (IR). We demonstrated that long-lived HSC, in contrast to short-lived myeloid progenitors, have enhanced expression of pro-survival members of the bcl2 gene family and robust induction of p53-mediated DNA damage response, which ensures their specific survival and repair following IR exposure. We reasoned that HSC have other unique protective features, which allow them to contend with a variety of cellular insults and damaged cellular components while maintaining their lifelong functionality and genomic integrity. We will present some of our recent findings on the fundamental mechanisms of stress-response that preserve HSC fitness during periods of metabolic stress, and allow for survival and repair following environmental stress associated with DNA damaging agents. It is now clear that oncogenic insults in diseases such as myeloproliferative neoplasms (MPN) can transform HSC and dramatically alter their biological functions leading to the emergence of leukemia-initiating stem cells (LSC), which are left untouched by most current therapies and can thereby mediate disease relapse. We will also discuss how transformed HSC may take advantage of some deregulated features of these normal stress-response mechanisms to escape therapeutic killing.