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.

Griggio, V., Vitale, C., Todaro, M., Riganti, C., Kopecka, J., Salvetti, C., Bomben, R., Dal Bo, M., Magliulo, D., Rossi, D., Pozzato, G., Bonello, L., Marchetti, M., Omedè, P., Kodipad, A. A., Laurenti, L., Del Poeta, G., Mauro, F. R., Bernardi, R., Zenz, T., Gattei, V., Gaidano, G., Foà, R., Massaia, M., Boccadoro, M., Coscia, M., HIF-1α is overexpressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia, <<HAEMATOLOGICA>>, 2019; (9): N/A-N/A. [doi:10.3324/haematol.2019.217430] [http://hdl.handle.net/10807/142668]

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

Laurenti, Luca;Foà, Robin;
2019

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.
2019
Inglese
Griggio, V., Vitale, C., Todaro, M., Riganti, C., Kopecka, J., Salvetti, C., Bomben, R., Dal Bo, M., Magliulo, D., Rossi, D., Pozzato, G., Bonello, L., Marchetti, M., Omedè, P., Kodipad, A. A., Laurenti, L., Del Poeta, G., Mauro, F. R., Bernardi, R., Zenz, T., Gattei, V., Gaidano, G., Foà, R., Massaia, M., Boccadoro, M., Coscia, M., HIF-1α is overexpressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia, <<HAEMATOLOGICA>>, 2019; (9): N/A-N/A. [doi:10.3324/haematol.2019.217430] [http://hdl.handle.net/10807/142668]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/142668
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