title: Human TM9SF4 Is a New Gene Down-Regulated by Hypoxia and Involved in Cell Adhesion of Leukemic Cells.
abstract: BACKGROUND
  The transmembrane 9 superfamily protein member 4, TM9SF4, belongs to the TM9SF family of proteins highly conserved through evolution. TM9SF4 homologs, previously identified in many different species, were mainly involved in cellular adhesion, innate immunity and phagocytosis. In human, the function and biological significance of TM9SF4 are currently under investigation. However, TM9SF4 was found overexpressed in human metastatic melanoma and in a small subset of acute myeloid leukemia (AMLs) and myelodysplastic syndromes, consistent with an oncogenic function of this gene.
  In this study, we first analyzed the expression and regulation of TM9SF4 in normal and leukemic cells and identified TM9SF4 as a gene highly expressed in human quiescent CD34+ hematopoietic progenitor cells (HPCs), regulated during monocytic and granulocytic differentiation of HPCs, both lineages giving rise to mature myeloid cells involved in adhesion, phagocytosis and immunity. Then, we found that TM9SF4 is markedly overexpressed in leukemic cells and in AMLs, particularly in M2, M3 and M4 AMLs (i.e., in AMLs characterized by the presence of a more or less differentiated granulocytic progeny), as compared to normal CD34+ HPCs. Proliferation and differentiation of HPCs occurs in hypoxia, a physiological condition in bone marrow, but also a crucial component of cancer microenvironment. Here, we investigated the impact of hypoxia on TM9SF4 expression in leukemic cells and identified TM9SF4 as a direct target of HIF-1α, downregulated in these cells by hypoxia. Then, we found that the hypoxia-mediated downregulation of TM9SF4 expression is associated with a decrease of cell adhesion of leukemic cells to fibronectin, thus demonstrating that human TM9SF4 is a new molecule involved in leukemic cell adhesion.
  
  
  CONCLUSIONS
  Altogether, our study reports for the first time the expression of TM9SF4 at the level of normal and leukemic hematopoietic cells and its marked expression at the level of AMLs displaying granulocytic differentiation.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Paolillo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Spinello
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Quaranta
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Pelosi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo Coco
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine of Istituto Superiore di Sanità, 00161, Rome, Italy.
authors.forename: Catherine
authors.initials: C
authors.lastname: Labbaye
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D003001:Cloning, Molecular; D005353:Fibronectins / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D005353:Fibronectins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C547837:TM9SF4 protein, human; D010100:Oxygen