TY - JOUR
T1 - HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment
AU - Valsecchi, Roberta
AU - Coltella, Nadia
AU - Belloni, Daniela
AU - Ponente, Manfredi
AU - Ten Hacken, Elisa
AU - Scielzo, Cristina
AU - Scarfò, Lydia
AU - Bertilaccio, Maria Teresa Sabrina
AU - Brambilla, Paola
AU - Lenti, Elisa
AU - Boneschi, Filippo Martinelli
AU - Brendolan, Andrea
AU - Ferrero, Elisabetta
AU - Ferrarini, Marina
AU - Ghia, Paolo
AU - Tonon, Giovanni
AU - Ponzoni, Maurilio
AU - Caligaris-Cappio, Federico
AU - Bernardi, Rosa
N1 - Publisher Copyright:
© 2016 by The American Society of Hematology.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2015-07-657056
DO - 10.1182/blood-2015-07-657056
M3 - Article
C2 - 26825709
AN - SCOPUS:84993661726
SN - 0006-4971
VL - 127
SP - 1987
EP - 1997
JO - Blood
JF - Blood
IS - 16
ER -