title: Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy.
abstract: High expression of the chemokine receptor 4, CXCR4, associated with a negative prognosis in acute myeloid leukemia, is related to hypoxia. Because CXCR4 expression is under the post-transcriptional control of microRNA-146a in normal and leukemic monocytic cells, we first investigated the impact of hypoxia on microRNA-146a and CXCR4 expression during monocytopoiesis and in acute monocytic leukemia. We then analyzed the effects of hypoxia on drug sensitivity of CXCR4-expressing leukemic cells. We found that microRNA-146a is a target of hypoxia-inducible factor-1α or -2α in relation to the stage of monocytopoiesis and the level of hypoxia, and demonstrated the regulation of the microRNA-146a/CXCR4 pathway by hypoxia in monocytes derived from CD34(+) cells. Thus, in myeloid leukemic cell lines, hypoxia-mediated control of the microRNA-146a/CXCR4 pathway depends only on the capacity of hypoxia-inducible factor-1α to up-regulate microRNA-146a, which in turn decreases CXCR4 expression. However, at variance with normal monocytic cells and leukemic cell lines, in acute monocytic leukemia overexpressing CXCR4, hypoxia up-modulates microRNA-146a but fails to down-modulate CXCR4 expression. We then investigated the effect of hypoxia on the response of leukemic cells to chemotherapy alone or in combination with stromal-derived factor-1α. We found that hypoxia increases stromal-derived factor-1α-induced survival of leukemic cells by decreasing their sensitivity to anti-leukemic drugs. Altogether, our results demonstrate that hypoxia-mediated regulation of microRNA-146a, which controls CXCR4 expression in monocytic cells, is lost in acute monocytic leukemia, thus contributing to maintaining CXCR4 overexpression and protecting the cells from anti-leukemic drugs in the hypoxic bone marrow microenvironment.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Spinello
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Quaranta
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Paolillo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Pelosi
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cerio
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Ernestina
authors.initials: E
authors.lastname: Saulle
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, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, University of Rome "Tor Vergata", Rome, Italy catherine.labbaye@iss.it.
authors.forename: Catherine
authors.initials: C
authors.lastname: Labbaye
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D020298:U937 Cells; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D019718:Receptors, CXCR4; D000099162:Endothelial PAS Domain-Containing Protein 1; C527276:CXCR4 protein, human; C497442:HIF1A protein, human; C542542:MIRN146 microRNA, human