TY - JOUR AU - Valentina Griggio, AU - Candida Vitale, AU - Maria Todaro, AU - Chiara Riganti, AU - Joanna Kopecka, AU - Chiara Salvetti, AU - Riccardo Bomben, AU - Michele Dal Bo, AU - Daniela Magliulo, AU - Davide Rossi, AU - Gabriele Pozzato, AU - Lisa Bonello, AU - Monia Marchetti, AU - Paola Omedè, AU - Ahad Ahmed Kodipad, AU - Luca Laurenti, AU - Giovanni Del Poeta, AU - Francesca Romana Mauro, AU - Rosa Bernardi, AU - Thorsten Zenz, AU - Valter Gattei, AU - Gianluca Gaidano, AU - Robin Foà, AU - Massimo Massaia, AU - Mario Boccadoro, AU - Marta Coscia, PY - 2020/03/31 Y2 - 2024/03/29 TI - HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia JF - Haematologica JA - haematol VL - 105 IS - 4 SE - Articles DO - 10.3324/haematol.2019.217430 UR - https://haematologica.org/article/view/9339 SP - 1042-1054 AB - In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-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 (TP53dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL 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 TP53dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53dis 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. ER -