The Leukemia-associated Mll-Ell Oncoprotein Induces Fibroblast Growth Factor 2 (Fgf2)-dependent Cytokine Hypersensitivity in Myeloid Progenitor Cells

Chirag A Shah,Ling Bei,Hao Wang,Leonidas C Platanias,Elizabeth A Eklund

doi:10.1074/jbc.m113.496109

Abstract

The subset of acute myeloid leukemias (AML) with chromosomal translocations involving the MLL gene have a poor prognosis (referred to as 11q23-AML). The MLL fusion proteins that are expressed in 11q23-AML facilitate transcription of a set of HOX genes, including HOXA9 and HOXA10. Because Hox proteins are transcription factors, this suggests the possibility that Hox target genes mediate the adverse effects of MLL fusion proteins in leukemia. Identifying such Hox target genes might provide insights to the pathogenesis and treatment of 11q23-AML. In the current study we found that Mll-Ell (an MLL fusion protein) induced transcriptional activation of the FGF2 gene in a HoxA9- and HoxA10-dependent manner. FGF2 encodes fibroblast growth factor 2 (also referred to as basic fibroblast growth factor). Fgf2 influences proliferation and survival of hematopoietic stem cells and myeloid progenitor cells, and increased Fgf2-expression has been described in AMLs. We determined that expression of Mll-Ell in myeloid progenitor cells resulted in autocrine production of Fgf2 and Fgf2-dependent cytokine hypersensitivity. Therefore, our results implicated increased Fgf2 expression in progenitor proliferation and expansion in 11q23-AML. Because small molecule inhibitors of Fgf-receptors are in human clinical trials, this suggested a potential therapeutic approach to this treatment refractory leukemia.

Highlights

MLL fusion proteins, including Mll-Ell, induce overexpression of HoxA9 and HoxA10 in the bone marrow
Because we previously found that HoxA9 and HoxA10 regulated CYBB transcription in a differentiation stage-specific manner, transfectants were assayed with or without differentiation to granulocytes with retinoic acid and dimethyl formamide (RA/DMF) [39]
There was a trend to increased activity with differentiation that did not meet statistical significance for either the proximal or distal cis element with overexpression of these Hox proteins (p Ն 0.07, n ϭ 6) (Fig. 3B). Consistent with the latter results, WT HoxA9 or HoxA10 was only slightly more efficient in activating the cis elements in comparison to HD-Tyr mutant forms of these proteins (p Ն 0.09, n ϭ 6; Fig. 3B). These results indicated that Mll-Ell influenced two FGF2 cis elements that were activated by HoxA9 and/or HoxA10

Summary

Introduction

MLL fusion proteins, including Mll-Ell, induce overexpression of HoxA9 and HoxA10 in the bone marrow. Results: Mll-Ell induces HoxA9-and HoxA10-dependent FGF2 transcription. Autocrine production of Fgf contributes to cytokine hypersensitivity in Mll-Ell expressing myeloid progenitor cells. Because Hox proteins are transcription factors, this suggests the possibility that Hox target genes mediate the adverse effects of MLL fusion proteins in leukemia. Identifying such Hox target genes might provide insights to the pathogenesis and treatment of 11q23-AML. Fgf influences proliferation and survival of hematopoietic stem cells and myeloid progenitor cells, and increased Fgf2expression has been described in AMLs. We determined that expression of Mll-Ell in myeloid progenitor cells resulted in autocrine production of Fgf and Fgf2-dependent cytokine hypersensitivity. Because small molecule inhibitors of Fgf-receptors are in human clinical trials, this suggested a potential therapeutic approach to this treatment refractory leukemia

Methods

Results

Conclusion