Distinct Mechanisms Regulate the Expression of flt3 Gene in Normal and Leukaemia-Like Stem Cells.

Abstract 4586

The interaction between the tyrosine kinase receptor Flt3 and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells (HSCs). Consequent to mutations or over-expression, constitutive activation of the Flt3/FL pathway is also a key factor in the enhanced survival and expansion of leukaemic cells. Flt3 expression is in particular a feature of Acute Myeloid Leukemia (AML) as it is found in the vast majority of cases. As well as a powerful inducer of leukaemogenesis, Flt3 expression could therefore be viewed as a measurable consequence of the leukaemic transcriptional programme. Hence, understanding its transcriptional regulation would improve our knowledge of the molecular events underlying normal stem cell commitment and AML disease. Accounting for 40% of AML cases, normal cytogenetic AML (NC-AML) is a heterogeneous group of diseases that present a number of different alterations in transcriptional regulators of haematopoiesis, including mutations (MLL, C/EBPα, AML1, PU.1, GATA-1) or altered expression brought about by silencing (C/EBPα, PU.1) or activation (MN1, MLL, ERG1, Cdx2, Hox proteins). Here, we show that a substantial number of these transcription factors are implicated in the regulation of the flt3 gene, and by comparing cell line models of normal HSCs and AML, we pinpoint the importance of HoxA9, Meis1, C/EBPα and c-Myb, and remodelling of the epigenetic environment in the regulation of flt3 expression in leukaemic cells. C/EBPa mutations are found in 10% of AML cases and are considered to be associated with a good prognosis in the absence of Flt3 constitutive activation. We present a model linking C/EBPα and c-Myb activity to flt3 gene expression and FLT3 signalling.