HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

被引:54
作者
Valsecchi, Roberta [1 ,2 ]
Coltella, Nadia [1 ]
Belloni, Daniela [1 ]
Ponente, Manfredi [1 ]
ten Hacken, Elisa [1 ,6 ]
Scielzo, Cristina [1 ]
Scarfo, Lydia [1 ]
Bertilaccio, Maria Teresa Sabrina [1 ]
Brambilla, Paola [3 ]
Lenti, Elisa [1 ]
Boneschi, Filippo Martinelli [3 ]
Brendolan, Andrea [1 ]
Ferrero, Elisabetta [1 ]
Ferrarini, Marina [1 ]
Ghia, Paolo [1 ,2 ,3 ,4 ]
Tonon, Giovanni [1 ]
Ponzoni, Maurilio [4 ,5 ]
Caligaris-Cappio, Federico [1 ,2 ,3 ,4 ]
Bernardi, Rosa [1 ]
机构
[1] Ist Sci San Raffaele, IRCCS, Div Expt Oncol, I-20132 Milan, Italy
[2] Univ Modena & Reggio Emilia, Dept Biomed Metab & Neural Sci, Modena, Italy
[3] Ist Sci San Raffaele, IRCCS, Div Neurosci, I-20132 Milan, Italy
[4] Univ Vita Salute San Raffaele, Sch Med, Milan, Italy
[5] Ist Sci San Raffaele, IRCCS, Pathol Unit, I-20132 Milan, Italy
[6] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
关键词
HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; ENDOTHELIAL GROWTH-FACTOR; MULTIPLE-MYELOMA; IN-VITRO; CLL; EXPRESSION; ANGIOGENESIS; SPECIFICITY; PROGRESSION; PROMOTES;
D O I
10.1182/blood-2015-07-657056
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha is transcriptionally regulated after coculture with stromal cells. Furthermore, HIF-1 alpha messenger RNA levels vary significantly within CLL patients and correlate with the expression of HIF-1 alpha target genes, including CXCR4, thus further emphasizing the relevance of HIF-1 alpha expression to CLL pathogenesis.
引用
收藏
页码:1987 / 1997
页数:11
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