Targeting HIF-1α 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-1α 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-1α and its regulatory pathways possibly represent appealing targets in the quest for novel strategies to overcome microenvironment-mediated tumor support in CLL. ABSTRACT: 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 α subunit of HIF-1 (HIF-1α) 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-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α 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-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α 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-1α 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.