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

Abstract

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 (TP53 dis) 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 TP53 dis 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 TP53 dis 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 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.

• Authors: Valentina Griggio, Candida Vitale, Maria Todaro, Chiara Riganti, Joanna Kopecka, Chiara Salvetti, Riccardo Bomben, Michele Dal Bo, Daniela Magliulo, Davide Rossi, Gabriele Pozzato, Lisa Bonello, Monia Marchetti, Paola Omedè, Ahad Ahmed Kodipad, Luca Laurenti, Giovanni Del Poeta, Francesca Romana Mauro, Rosa Bernardi, Thorsten Zenz, Valter Gattei, Gianluca Gaidano, Robin Foà, Massimo Massaia, Mario Boccadoro, Marta Coscia
• Journal: Haematologica (Haematologica) Vol. 105 Issue 4 Pg. 1042-1054 (04 2020) ISSN: 1592-8721 [Electronic] Italy
• PMID: 31289209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2020 Ferrata Storti Foundation.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• TP53 protein, human
• Tumor Suppressor Protein p53
• Von Hippel-Lindau Tumor Suppressor Protein

Topics

• Animals
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics)
• Mice
• Phosphatidylinositol 3-Kinases (genetics)
• Tumor Microenvironment
• Tumor Suppressor Protein p53 (genetics)
• Von Hippel-Lindau Tumor Suppressor Protein