Regulation of Hematopoietic Stem Cell Aging by the E3 ubiquitin Ligase Fbw7

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DESCRIPTION (provided by applicant): All tissues contain stem and progenitor cell populations, which are guided by intrinsic and extrinsic cues. Pluripotent embryonic stem cells generate all tissues in an organism while adult stem cells work to sustain organ function by maintaining tissue homeostasis. Aging is characterized by a gradual decline in organ function. Since a primary role of adult stem cells is to sustain tissue integrity, they inevitably contribute to this phenomenon. The hematopoietic system is one example of how a stem cell changes to support a healthy immune system through life. Identifying signaling pathways that regulate hematopoietic stem cell (HSC) self-renewal and differentiation at different stages of life (fetal, "young" adult, and "old" adult HSCs) will shed light on pathways that regulate organ/tissue function. The E3 ligase, Fbw7, has been shown to influence HSC self-renewal through the regulation of c-Myc protein. c-Myc abundance was a hallmark of quiescent "young" adult HSCs and was up-regulated during differentiation. c-Myc protein abundance differed in HSCs from fetal, "young" adult" and "old" adult mice. Notably, c-Myc protein was expressed at higher levels in "old" adult HSCs when compared to "young" adult counterparts, suggesting an altered quiescent status. Myeloid leukemias, such as chronic myelogenous leukemia (CML), arise when a BcrAbl translocation occurs within HSCs. Interestingly, CML predominately arises in patients that are >60 years of age, possibly implicating an aged HSC as the source of transformation. In this proposal, we hypothesize that Fbw7 substrate interactions maintain a critical balance between self-renewal and differentiation in HSCs from different age groups and that Fbw7 is a putative therapeutic target in CML. PUBLIC HEALTH RELEVANCE: The research proposed has significant implications in both the field of aging and blood related malignancies. This work is intended to identify important pathways that regulate hematopoietic stem cell function in mice of different age groups. This work will also address how these pathways may impact age related diseases such as chronic myelogenous leukemia.