The transcription factor E47 controls the cell cycle quiescence and development of multipotent hematopoietic progenitors (138.3)

Abstract

Abstract It is of great interest to understand the mechanisms controlling the development and maintenance of multi-potential bone marrow progenitors, the key hematopoietic compartment that seeds the entire immune system. Using E47 knockout (KO) mice, we found that the transcription factor E47 plays a critical role in the cell cycle regulation and development of the multipotent hematopoietic subsets. Multipotent LSKs (Lineage-Sca-1+c-Kit+) from E47 KO mice had significantly increased BrdU incorporation, decreased proportion of progenitors in G0, and hypersensitivity to a mitotoxin 5-Fluorouracil, suggesting loss of cell cycle quiescence. Total LSKs contain both self-renewing hematopoietic stem cells (HSCs) and non-renewing multipotential progenitors (MPPs). Using three independent phenotypic definitions, we found that E47 KO mice have numerically unperturbed HSCs but a 2-4 fold reduction in the MPPs. Moreover, the residual MPPs in E47 KO mice fail to fully up-regulate flk2 and lack V(D)J rearrangement, suggesting compromised lymphoid differentiation potential. Finally, both loss-of-function and gain-of-function experiments identified a key stem cell regulator, p21, as E47 target in the multipotent LSKs. Taken together, our data define an important role of the transcription factor E47 in controlling the development, differentiation and cell cycle regulation of multipotent hematopoietic progenitors.