title: Cooperation between AlphavBeta3 integrin and the fibroblast growth factor receptor enhances proliferation of Hox-overexpressing acute myeloid leukemia cells.
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.
authors.affiliation: The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Chirag A
authors.initials: CA
authors.lastname: Shah
authors.affiliation: The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Jesse Brown Veteran's Administration Medical Center, Chicago, IL, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Bei
authors.affiliation: The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Altman
authors.affiliation: The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Jesse Brown Veteran's Administration Medical Center, Chicago, IL, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Jesse Brown Veteran's Administration Medical Center, Chicago, IL, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
mesh_terms: D000208:Acute Disease; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics* / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism; D020298:U937 Cells
chemical_list: D018398:Homeodomain Proteins; D039302:Integrin alphaVbeta3; C472772:MLL-ELL fusion protein, human; D015514:Oncogene Proteins, Fusion; D017468:Receptors, Fibroblast Growth Factor; D051788:Myeloid-Lymphoid Leukemia Protein
keywords: fibroblast growth factor; homeobox; integrin; leukemia; transcription factor