Hematopoietic stem cell aging and leukemogenesis

Abstract

Age is the single most important prognostic factor associated with many cancers, including most leukemias and lymphomas. Aging is also associated with dramatic changes in hematopoiesis. As all mature hematopoietic cells are derived from multipotent hematopoietic stem cells (HSCs), age-dependent changes inthese cells likely contribute to both alterations in hematopoiesis and increases in blood cancers. In this chapter, we will review the various changes in both HSCs and their microenvironments that could underlie the striking association between multiple major hematopoietic malignancies and old age. Traditionally, the association between aging and cancer has been explained by the requirement for sufficient time for the requisite number of oncogenic mutations to accumulate, as these mutationsare thought to limit cancer incidence. We will describe how other aging-associated changes in hematopoietic stem/progenitor cells and their niches, including alterations in cellular fitness, inflammation, localization, and differentiation, could substantially impact age-dependent leukemogenesis. Aging of the hematopoietic system is highly complicated and multifactorial, and likewise increased leukemogenesis in the elderly will likely belie simpleexplanations.