LYMPHOID NEOPLASIA HIF-1 a regulates the interaction of chronic lymphocytic leukemia cells with the tumor microenvironment

hypoxia and are often activated in solid and hematologic malignancies due to intratumoral hypoxia and emerging new layers of regulation. We found that in chronic lymphocytic leukemia (CLL), HIF-1 a 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 unbiasedmicroarrayanalysis,wefoundthatinCLLcells,HIF-1 a regulatestheexpression 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 a 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 a is transcriptionally regulatedaftercoculturewithstromalcells.Furthermore,HIF-1 a messengerRNAlevelsvarysignificantlywithinCLLpatientsandcorrelate with the expression of HIF-1 a target genes, including CXCR4, thus further emphasizing the relevance of HIF-1 a expression to CLL pathogenesis. ( Blood . 2016;127(16):1987-1997) Histopathology and immunohistochemistry Mice tissues were xed 4% formalin, paraf n embedded, 5- Immunohistochemistry performed CD31 antibody (Thermo Scien-ti fi edpathologistevaluatedhistologicsections.Imagesweretaken with a Zeiss Axioskop 40 microscope equipped with a Zeiss AxioCam MRc digital camera. Statistics measure cance.Forsurvivalexperiments,Kaplan-Meiercurveswereanalyzedwith