Regulation of hematopoietic stem cell fate by the ubiquitin proteasome system

Hematopoietic stem cells (HSCs) residing in the bone marrow generate mature blood cells throughout the life of the organism. This is accomplished by careful regulation of HSC activity to balance quiescence, self-renewal and differentiation. Studies of the molecular mechanisms governing HSC maintenance have mostly focused on the role of signaling and transcriptional processes. However, it has recently been demonstrated that protein regulation via the ubiquitin proteasome system (UPS) is crucial for normal HSC function; the loss of which can lead to transformation and leukemogenesis. The effective use of a general and reversible inhibitor of the UPS, bortezomib, in treating mantle cell lymphoma and multiple myeloma has demonstrated that targeting the UPS has therapeutic potential. Thus, understanding the emerging field of how the UPS regulates HSC activity may lead to novel targets for therapy of leukemia.