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

• Published in: Oncotarget Vol. 7; no. 34; pp. 54782 - 54794
• Main Authors: Shah, Chirag A., Bei, Ling, Wang, Hao, Altman, Jessica K., Platanias, Leonidas C., Eklund, Elizabeth A.
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 23.08.2016
• Subjects: Acute Disease; Animals; Cell Proliferation - genetics; Cells, Cultured; Gene Expression Regulation, Leukemic; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Integrin alphaVbeta3 - genetics; Integrin alphaVbeta3 - metabolism; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Mice, Inbred C57BL; Myeloid Progenitor Cells - metabolism; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Promoter Regions, Genetic - genetics; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; Research Paper; RNA Interference; U937 Cells; leukemia; transcription factor; homeobox; fibroblast growth factor; integrin
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10189

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.