In chronic lymphocytic leukemia, the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumour cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study we demonstrate that chronic lymphocytic leukemia cells from TP53-disrupted (TP53dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1 α) and increased HIF-1 transcriptional activity, compared to the wild type counterpart. In the TP53dis subset, HIF-1 α upregulation is due to reduced expression of the HIF-1 α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently from the 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 tumour cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumour activity in Eμ-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 evidences for its further investigation as a potential new drug in chronic lymphocytic leukemia.

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

Griggio, Valentina
Co-first
;
Vitale, Candida
Co-first
;
Todaro, Maria;Riganti, Chiara;Kopecka, Joanna;Salvetti, Chiara;Bonello, Lisa;Massaia, Massimo;Boccadoro, Mario;Coscia, Marta
Last
2020

Abstract

In chronic lymphocytic leukemia, the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumour cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study we demonstrate that chronic lymphocytic leukemia cells from TP53-disrupted (TP53dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1 α) and increased HIF-1 transcriptional activity, compared to the wild type counterpart. In the TP53dis subset, HIF-1 α upregulation is due to reduced expression of the HIF-1 α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently from the 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 tumour cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumour activity in Eμ-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 evidences for its further investigation as a potential new drug in chronic lymphocytic leukemia.
105
1042
1054
CLL microenvironment; Chronic Lymphocytic Leukemia; Hypoxia inducible factor-1a; ibrutinib; p53 abnormalities
Griggio, Valentina; Vitale, Candida; Todaro, Maria; Riganti, Chiara; Kopecka, Joanna; Salvetti, Chiara; Bomben, Riccardo; Dal Bo, Michele; Magliulo, Daniela; Rossi, Davide; Pozzato, Gabriele; Bonello, Lisa; Marchetti, Monia; Omedè, Paola; Kodipad, Ahad Ahmed; Laurenti, Luca; Del Poeta, Giovanni; Mauro, Francesca Romana; Bernardi, Rosa; Zenz, Thorsten; Gattei, Valter; Gaidano, Gianluca; Foà, Robin; Massaia, Massimo; Boccadoro, Mario; Coscia, Marta
File in questo prodotto:
File Dimensione Formato  
Griggio, AOP MS and Supporting 2019.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 3.08 MB
Formato Adobe PDF
3.08 MB Adobe PDF Visualizza/Apri
Griggio, Haemotologica MS and Supporting 2020.pdf

Accesso aperto

Descrizione: Griggio, Haematologica 2020
Tipo di file: PDF EDITORIALE
Dimensione 11.34 MB
Formato Adobe PDF
11.34 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1720959
Citazioni
  • ???jsp.display-item.citation.pmc??? 22
  • Scopus 22
  • ???jsp.display-item.citation.isi??? 25
social impact