Targeting Hif-1 Alpha Regulatory Pathways As A Strategy To Hamper Tumor-Microenvironment Interactions In Cll

Simple Summary In chronic lymphocytic leukemia (CLL), the interplay between the neoplastic clone and the tumor microenvironment largely contributes to leukemia survival, tumor propagation and drug resistance. A better understanding of the molecular circuits sustaining the biological effects of this microenvironment-induced support is fundamental for designing targeted treatment strategies that can be beneficial, especially for high-risk patients who fail standard therapy. In our study, we show that the targeting of the transcription factor HIF-1 alpha or its regulatory pathways disrupts the mutual interactions occurring between the tumor microenvironment and CLL cells and exerts anti-tumor effects, by acting both at the leukemic cell- and stromal cell-level. HIF-1 alpha and its regulatory pathways possibly represent appealing targets in the quest for novel strategies to overcome microenvironment-mediated tumor support in CLL.The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the alpha subunit of HIF-1 (HIF-1 alpha) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1 alpha upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1 alpha inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1 alpha was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1 alpha target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1 alpha or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells.