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

Hypoxia-inducible transcription factors (HIFs) regulateawidearray of adaptiveresponses 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,wefound that inCLLcells, HIF-1αregulates 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 inmice. Of interest, we found that in CLL cells, HIF-1α is transcriptionally regulatedafter coculture with stromal cells.Furthermore,HIF-1αmessengerRNAlevels varysignificantly withinCLLpatientsandcorrelate with the expression of HIF-1α target genes, including CXCR4, thus further emphasizing the relevance of HIF-1α expression to CLL pathogenesis. [ABSTRACT FROM AUTHOR]