Regulation of proliferation and survival of B-lymphocytes by Ebf1 - implications in leukaemia

Abstract

Ebf1 is an important determinant of the specification of B lymphocytes. However, expression of this transcription factor is not limited to early B lymphopoiesis and constitutive deletion of Ebf1 results in developmental block and embryonic lethality. To gain insight into additional functions of Ebf1, we inactivated Ebf1 at various stages of differentiation using a Cre-lox-regulated conditional knockout allele. We found that Ebf1 is required for the proliferation and survival of pro-B cells and peripheral B-cell subsets. In Ebf1-deficient pro-B cells, overexpression of the pro-survival genes Bcl2 or BclXL was not sufficient for cell–survival. We found a remarkable clonal difference in the cell cycle response of transformed pro-B cells upon induced Ebf1-deletion: one cell type arrested in the G(1) phase and the other type died without arrest. Unexpectedly, the cycling cell-type survived upon c-myb overexpression, in contrast to the other transformed clone type or to primary pro-B cells, showing cell cycle arrest as well. This point to two different Ebf1 regulated cell-cycle-coupled cell survival pathways. As inactivating mutations of the EBF1 gene are frequent in acute lymphoblastic leukaemia, elucidating the role of Ebf1 in cell cycle and survival could provide novel means of intervention in the growth of leukaemia cells.