Search

In hematopoiesis, self-renewal, proliferation, differentiation and apoptosis represent opposing decisions made by stem cells and progenitor cells, which when dysregulated can result in leukaemia. Here, we have investigated the function of Myb proteins in regulating these key cellular decisions, using the cell line FDCP-mix A4 as a model of early hematopoiesis. High concentrations of IL-3 in these cells favour self-renewal over differentiation and apoptosis. However when endogenous Myb activity was inhibited with an inducible dominant interfering protein, self-renewal was replaced by apoptosis and differentiation. Differentiation was to granulocytes and monocyte/macrophages and was closely associated with a G1-S phase block in the cell cycle. As for normal hematopoiesis, cytokine-induced terminal differentiation of FDCP-mix cells is associated with concomitant proliferation prior to its completion. However, when Myb activity was inhibited during this process, proliferation and survival were both reduced, resulting in a much lower yield of mature cells. These results indicate multiple cellular roles of Myb proteins during normal hematopoiesis.

Hematopoiesis, the process by which mature blood cells arise, is controlled by multiple transcription factors, which act in stage- and lineage-specific complexes. It is a major goal to elucidate the genes regulated by these transcription factors, in order to obtain a full understanding of the process and its malignant counterpart, leukemia. Myb family transcription factors play a central role in hematopoiesis. To identify new Myb family target genes, we have used an inducible dominant-negative protein for a subtraction cloning protocol in a model cell system (FDCP-Mix) with many characteristics of normal hematopoiesis. We present here a novel group of 29 validated Myb family target genes of diverse functions.