Regulation of the histone 4 epigenetic landscape upon hematopoietic stem cell aging

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There is a marked increase in the incidence of acute myelogenous leukemia (AML) with age. AML is thus an aging-related disease. Also, the nature of the AML in the elderly (70+) is usually distinct from AML found in younger patients. Multiple theories have been put forward to explain both the increased incidence and the change in nature of AML upon aging. One prominent theory is that the underlying stem cell associated with AML, the hematopoietic stem cell (HSC) ages, and with aging there is reduced genetic and/or epigenetic stability. While there is a small, but significant increase in genetic mutations upon aging, changes in the epigenetic landscape upon aging have just begun to be unraveled over the last couple of years. It is assumed that alterations in the epigenome are causative for changes in self-renewal and differentiation of HSCs and leukemic stem cells. Epigenetic marks can be pharmacologically modified, which render them potential targets to influence aging-related leukemia. Unfortunately, little is known about what genes and mechanisms regulate of changes in the epigenetic make-up of HSCs upon aging. Identification of these players might become a pre-requisite to design rational approaches to influence aging-related changes in the epigenetic signature of HSCs, and to target these changes in aging-related leukemia like AML. This projects aims at the identification at modifiers of the H4K16ac landscape that is changed in aged HSCs and will test their action on leukemia initiation and progression. We will employ comparative sequencing approaches as well as a genetic approach based on HSCs from murine recombinant inbred (RI) strains to ultimately unravel driver genetic events that contribute to changes in the epigenetic landscape of Histone 4 in HSCs upon aging, and will determine the extent to which they contribute to AML initiation/progression.