Down-regulation of Hox A7 is required for cell adhesion and migration on fibronectin during early HL-60 monocytic differentiation.
Hox genes, which are key regulators of cell fate and pattern formation during embryogenesis, are also important regulators of hematopoiesis, and different combinations of Hox gene products are involved in lineage commitment or maturation. However, their molecular and cellular modes of action are not yet completely understood. Recent studies have indicated that Hox genes are involved in the regulation of cell-extracellular matrix (ECM) interactions and cell migration. Here, we report that Hox A7, a gene frequently overexpressed in acute myeloid leukemia, is down-regulated during HL-60 monocytic differentiation. Using a model in which HL-60 cells are induced to differentiate toward the monocytic lineage with bone marrow stromal-like cells, we demonstrate that Hox A7-sustained expression disturbs the regulation of cell adhesive and migratory capacities on fibronectin during early differentiation. We show that this is accompanied by a partial blockage of the transcriptional induction of proline-rich tyrosine kinase 2, a gene coding for a focal adhesion kinase active in monocytes, and of tissue transglutaminase, a gene coding for a fibronectin coreceptor in monocytes. This is the first report that demonstrates the involvement of a Hox gene in the regulation of adhesion and migration of hematopoietic cells and that links it to the deregulation of genes involved in cell-ECM interactions and downstream signaling pathways.
Leroy
Pascale
P
INSERM U364, Faculty of Medicine, Nice, France. pleroy@itsa.ucsf.edu
Berto
Fréderick
F
Bourget
Isabelle
I
Rossi
Bernard
B
D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics*; D005353:Fibronectins / Q000378:metabolism* / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018922:HL-60 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism
D005353:Fibronectins; C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; D039081:Integrin alpha5beta1; D016023:Integrins; D009363:Neoplasm Proteins; D011503:Transglutaminases; C105804:transglutaminase 1; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C103547:PTK2B protein, human