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

Roberta Valsecchi, Nadia Coltella, Daniela Belloni, Manfredi Ponente, Elisa Ten Hacken, Cristina Scielzo, Lydia Scarfò, Maria Teresa Sabrina Bertilaccio, Paola Brambilla, Elisa Lenti, Filippo Martinelli Boneschi, Andrea Brendolan, Elisabetta Ferrero, Marina Ferrarini, Paolo Ghia, Giovanni Tonon, Maurilio Ponzoni, Federico Caligaris-Cappio, Rosa Bernardi

Research output: Contribution to journalArticle


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.

Original languageEnglish
Pages (from-to)1987-1997
Number of pages11
Issue number16
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

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    Valsecchi, R., Coltella, N., Belloni, D., Ponente, M., Ten Hacken, E., Scielzo, C., Scarfò, L., Bertilaccio, M. T. S., Brambilla, P., Lenti, E., Boneschi, F. M., Brendolan, A., Ferrero, E., Ferrarini, M., Ghia, P., Tonon, G., Ponzoni, M., Caligaris-Cappio, F., & Bernardi, R. (2016). HIF-1α regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment. Blood, 127(16), 1987-1997. https://doi.org/10.1182/blood-2015-07-657056