title: HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment.
abstract: Hypoxia-inducible transcription factors (HIFs) regulate a wide array of adaptive responses to hypoxia and are often activated in solid tumors and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1α is a novel regulator of the interaction of CLL cells with protective leukemia microenvironments and, in turn, is regulated by this interaction in a positive feedback loop that promotes leukemia survival and propagation. Through unbiased microarray analysis, we found that in CLL cells, HIF-1α regulates the expression of important chemokine receptors and cell adhesion molecules that control the interaction of leukemic cells with bone marrow and spleen microenvironments. Inactivation of HIF-1α impairs chemotaxis and cell adhesion to stroma, reduces bone marrow and spleen colonization in xenograft and allograft CLL mouse models, and prolongs survival in mice. Of interest, we found that in CLL cells, HIF-1α is transcriptionally regulated after coculture with stromal cells. Furthermore, HIF-1α messenger RNA levels vary significantly within CLL patients and correlate with the expression of HIF-1α target genes, including CXCR4, thus further emphasizing the relevance of HIF-1α expression to CLL pathogenesis.
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy; Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Valsecchi
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Nadia
authors.initials: N
authors.lastname: Coltella
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Belloni
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Manfredi
authors.initials: M
authors.lastname: Ponente
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Ten Hacken
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Cristina
authors.initials: C
authors.lastname: Scielzo
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Lydia
authors.initials: L
authors.lastname: Scarfò
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Maria Teresa Sabrina
authors.initials: MT
authors.lastname: Bertilaccio
authors.affiliation: Division of Neuroscience, IRCCS, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Brambilla
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Lenti
authors.affiliation: Division of Neuroscience, IRCCS, San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Filippo
authors.initials: F
authors.lastname: Martinelli Boneschi
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Brendolan
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrero
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Marina
authors.initials: M
authors.lastname: Ferrarini
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy; Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Division of Neuroscience, IRCCS, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University School of Medicine, Milan, Italy; and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Vita-Salute San Raffaele University School of Medicine, Milan, Italy; and Pathology Unit, IRCCS, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy; Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Division of Neuroscience, IRCCS, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University School of Medicine, Milan, Italy; and.
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.affiliation: Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute, Milan, Italy;
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002450:Cell Communication / Q000235:genetics*; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
references.citation: Open J Hematol. 2012;3(S1):null
references.pmid: 22844583
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Leukemia. 2010 Apr;24(4):872-6
references.pmid: 20072150
references.citation: Angiogenesis. 2011 Sep;14 (3):245-53
references.pmid: 21452059
references.citation: Blood. 2006 Aug 15;108(4):1334-8
references.pmid: 16670263
references.citation: J Clin Oncol. 2014 Sep 20;32(27):3039-47
references.pmid: 25049322
references.citation: FEBS Lett. 2012 Aug 31;586(18):2906-10
references.pmid: 22841548
references.citation: EMBO Mol Med. 2014 May 01;6(5):640-50
references.pmid: 24711541
references.citation: Haematologica. 2009 Oct;94(10):1456-9
references.pmid: 19794091
references.citation: Ann N Y Acad Sci. 2005 Dec;1062:1-12
references.pmid: 16461783
references.citation: J Cell Physiol. 2012 Feb;227(2):514-24
references.pmid: 21503885
references.citation: Br J Haematol. 1999 Dec;107(3):605-10
references.pmid: 10583266
references.citation: Semin Cancer Biol. 2014 Feb;24:43-8
references.pmid: 23831274
references.citation: Leukemia. 2013 Apr;27(4):961-4
references.pmid: 23212153
references.citation: J Cell Biochem. 2007 Apr 1;100(5):1109-18
references.pmid: 17131382
references.citation: Trends Pharmacol Sci. 2012 Apr;33(4):207-14
references.pmid: 22398146
references.citation: Blood. 2012 Jun 14;119(24):5782-94
references.pmid: 22394600
references.citation: Blood. 2008 Jun 15;111(12):5446-56
references.pmid: 18216293
references.citation: Semin Cancer Biol. 2014 Feb;24:71-81
references.pmid: 24018164
references.citation: PLoS One. 2013 Aug 26;8(8):e71613
references.pmid: 23990965
references.citation: PLoS Med. 2006 Mar;3(3):e47
references.pmid: 16417408
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10 ):6955-60
references.pmid: 12011454
references.citation: Blood. 2013 Mar 21;121(12):2264-73
references.pmid: 23325840
references.citation: J Clin Invest. 2012 Oct;122(10):3432-8
references.pmid: 23023714
references.citation: Curr Opin Cell Biol. 2012 Apr;24(2):232-5
references.pmid: 22296771
references.citation: Blood. 2009 May 28;113(22):5568-74
references.pmid: 19336759
references.citation: Clin Cancer Res. 2010 Oct 1;16(19):4809-21
references.pmid: 20702613
references.citation: Cancer Res. 2004 Oct 1;64(19):6845-8
references.pmid: 15466170
references.citation: Int Rev Cell Mol Biol. 2012;296:139-85
references.pmid: 22559939
references.citation: Diagn Pathol. 2008 Apr 18;3:16
references.pmid: 18423023
references.citation: Leuk Lymphoma. 2012 Oct;53(10):1988-98
references.pmid: 22397722
references.citation: Blood. 2000 Nov 1;96(9):3181-7
references.pmid: 11050001
references.citation: Cancer Res. 2004 Feb 15;64(4):1475-82
references.pmid: 14983893
references.citation: Clin Cancer Res. 2010 Dec 15;16(24):5928-35
references.pmid: 20962028
references.citation: Leukemia. 2000 Aug;14(8):1414-8
references.pmid: 10942237
references.citation: Blood. 2010 Feb 25;115(8):1605-9
references.pmid: 20018917
references.citation: J Clin Invest. 2013 Jan;123(1):189-205
references.pmid: 23318994
references.citation: Mol Cancer Res. 2014 Oct;12(10):1347-54
references.pmid: 25158954
references.citation: Nucleic Acids Res. 2009 Aug;37(14):4587-602
references.pmid: 19491311
references.citation: Mol Cancer Ther. 2008 Nov;7(11):3598-608
references.pmid: 18974394
references.citation: Cancer Cell. 2006 Apr;9(4):313-25
references.pmid: 16616336
references.citation: Nat Genet. 2000 Jun;25(2):217-22
references.pmid: 10835641
references.citation: Nat Rev Genet. 2009 Dec;10(12):821-32
references.pmid: 19884889
references.citation: Blood. 2016 Jan 21;127(3):279-86
references.pmid: 26576865