Cooperation between AlphavBeta3 integrin and the fibroblast growth factor receptor enhances proliferation of Hox-overexpressing acute myeloid leukemia cells

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// Chirag A. Shah 1 , Ling Bei 1, 2 , Hao Wang 1 , Jessica K. Altman 1 , Leonidas C. Platanias 1, 2 , Elizabeth A. Eklund 1, 2 1 The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 2 Jesse Brown Veteran’s Administration Medical Center, Chicago, IL, USA Correspondence to: Elizabeth A. Eklund, email: e-eklund@northwestern.edu Keywords: transcription factor, integrin, leukemia, homeobox, fibroblast growth factor Received: April 04, 2016      Accepted: June 03, 2016      Published: June 20, 2016 ABSTRACT A poor prognosis subtype of acute myeloid leukemia (AML) is characterized by increased expression of a set of homeodomain (HD) transcription factors, including HoxA9, HoxA10 and Cdx4. This encompasses AML with MLL1 gene translocations, because Mll1-fusion proteins aberrantly activate HOX transcription. We previously identified FGF2 (Fibroblast Growth Factor 2) as a target gene for HoxA9 and HoxA10 that was indirectly activated by Mll-Ell (an Mll1-fusion protein). Autocrine stimulation of Mll-Ell + myeloid progenitor cells by Fgf2 stabilized βcatenin and increased expression of βcatenin target genes, including CDX4 . Since HOXA9 and HOXA10 are Cdx4 target genes, Fgf2 indirectly augmented direct effects of Mll-Ell on these genes. ITGB3 , encoding β3 integrin, is another HoxA10 target gene. In the current studies, we found activation of ITGB3 transcription in Mll-Ell + myeloid progenitor cells via HoxA9 and HoxA10. Increased expression of αvβ3 integrin increased Syk-activation; contributing to cytokine hypersensitivity. However, inhibiting Fgf-R partly reversed αvβ3 activity in Mll-Ell + progenitor cells by decreasing ITGB3 promoter activity in a βcatenin- and Cdx4-dependent manner. Inhibitors of Fgf-R or Syk impaired proliferation of CD34 + bone marrow cells from AML subjects with increased Hox-expression; with a greater combined effect. These studies identified a rational therapeutic approach to this AML subtype.