HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia

In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIP-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53-disrupted (TP53(dis)) patients have constitutively higher expression levels of the alpha-subunit of HIP-1 (HIP-1 alpha) and increased HIP-1 transcriptional activity compared to the wild-type counterpart. In the TP53s subset, HIP-1 alpha upregulation is due to reduced expression of the HIF-1 alpha ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIP-1 alpha accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVH.I. and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53(dis) tumor cells. The HIF-1 alpha inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in ER-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53(dis) leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL.