HoxA10 Protein Regulates Transcription of Gene Encoding Fibroblast Growth Factor 2 (FGF2) in Myeloid Cells

Abstract

HoxA10 is a member of a highly conserved family of homeodomain transcription factors that are involved in definitive hematopoiesis and implicated in the pathogenesis of acute myeloid leukemia (AML). During normal hematopoiesis, HoxA10 facilitates myeloid progenitor expansion and impedes myeloid differentiation. To better understand the molecular mechanisms that control these events, we have been identifying and characterizing HoxA10 target genes. In this study, we identified the gene encoding fibroblast growth factor 2 (Fgf2 or basic fibroblast growth factor) as a target gene that is relevant to the biological effects of HoxA10. We identified two cis elements in the proximal FGF2 promoter that are activated by HoxA10 in myeloid progenitor cells and differentiating phagocytes. We determined that Fgf2 expression and secretion are regulated in a HoxA10-dependent manner in these cells. We found that increased Fgf2 production by HoxA10-overexpressing myeloid progenitor cells induced a phosphoinositol 3-kinase-dependent increase in β-catenin protein. This resulted in autocrine stimulation of proliferation in HoxA10-overexpressing cells and hypersensitivity to other cytokines that share this pathway. Therefore, these studies identified expression of Fgf2 as a mechanism by which HoxA10 controls the size of the myeloid progenitor population. These studies also suggested that aberrant production of Fgf2 may contribute to leukemogenesis in the subset of AML with dysregulated Hox expression. Therapeutic targeting of Fgf2-stimulated signaling pathways might be a rational approach to this poor prognosis subset of AML.