Page 200 - Haematologica April 2020

Chronic Lymphocytic Leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):1042-1054
HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia
Valentina Griggio,1,2* Candida Vitale,1,2* Maria Todaro,1,2 Chiara Riganti,3 Joanna Kopecka,3 Chiara Salvetti,1,2 Riccardo Bomben,4 Michele Dal Bo,4 Daniela Magliulo,5 Davide Rossi,6 Gabriele Pozzato,7 Lisa Bonello,2
Monia Marchetti,8 Paola Omedè,1 Ahad Ahmed Kodipad,9 Luca Laurenti,10 Giovanni Del Poeta,11 Francesca Romana Mauro,12 Rosa Bernardi,5 Thorsten Zenz,13 Valter Gattei,4 Gianluca Gaidano,9 Robin Foà,12
Massimo Massaia,14 Mario Boccadoro1,2 and Marta Coscia1,2
1Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy; 2Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy; 3Department of Oncology, University of Turin, Turin, Italy; 4Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy; 5Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; 6Department of Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland; 7Department of Internal Medicine and Hematology, Maggiore General Hospital, University of Trieste, Trieste, Italy; 8Hematology Day Service, Oncology SOC, Hospital Cardinal Massaia, Asti, Italy; 9Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy; 10Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy; 11Division of Hematology, S. Eugenio Hospital and University of Tor Vergata, Rome, Italy; 12Hematology, Department of Translational and Precision Medicine, Sapienza University, Policlinico Umberto I, Rome, Italy; 13Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland and 14Hematology Unit, ASO Santa Croce e Carle, Cuneo, Italy
*VG and CV contributed equally to this study.
ABSTRACT
In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their pro- tective 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 Eμ-TCL1 mice. BAY87-2243 also overcomes the constitutive fludara- bine 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.
Correspondence:
MARTA COSCIA
marta.coscia@unito.it
Received: February 1, 2019. Accepted: July 4, 2019. Pre-published: July 9, 2019.
doi:10.3324/haematol.2019.217430
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1042
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