@article{a6b6497b398442ed81d7af85361854ee,
title = "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 (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. {\textcopyright}2020 Ferrata Storti Foundation",
keywords = "2 (2 amino 3 methoxyphenyl)chromone, 2 morpholino 8 phenylchromone, 4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide, actin, CD19 antigen, enolase, enolase 1, fludarabine, glucose transporter 1, glyceraldehyde 3 phosphate dehydrogenase, hypoxia inducible factor 1alpha, ibrutinib, messenger RNA, mitogen activated protein kinase 1, mitogen activated protein kinase 3, protein p53, RhoA guanine nucleotide binding protein, ubiquitin protein ligase, unclassified drug, vasculotropin, von Hippel Lindau protein, animal cell, animal experiment, animal model, animal tissue, antineoplastic activity, apoptosis, Article, blood sampling, Burkitt lymphoma, cell activation, cell culture, cell death, cell isolation, cell viability assay, chronic lymphatic leukemia, comparative study, controlled study, cytosolic fraction, cytotoxicity, down regulation, gene expression, gene expression regulation, gene mutation, gene repression, gene set enrichment analysis, genetic analysis, genetic transcription, human, immuno enzymatic measurement, leukemia cell line, lymphatic leukemia, major clinical study, nonhuman, nuclear expression, oncogene c H ras, Pi3K/Akt signaling, protein degradation, real time polymerase chain reaction, signal transduction, stroma cell, survival factor, tumor microenvironment, upregulation, Western blotting",
author = "V. Griggio and C. Vitale and M. Todaro and C. Riganti and J. Kopecka and C. Salvetti and R. Bomben and M.D. Bo and D. Magliulo and D. Rossi and G. Pozzato and L. Bonello and M. Marchetti and P. Omed{\`e} and A.A. Kodipad and L. Laurenti and G.D. Poeta and F.R. Mauro and R. Bernardi and T. Zenz and V. Gattei and G. Gaidano and R. Fo{\`a} and M. Massaia and M. Boccadoro and M. Coscia",
note = "Cited By :8 Export Date: 11 March 2021 CODEN: HAEMA Correspondence Address: Coscia, M.; Division of Hematology, Italy; email: marta.coscia@unito.it Chemicals/CAS: 2 (2 amino 3 methoxyphenyl)chromone, 167869-21-8; 2 morpholino 8 phenylchromone, 154447-36-6; 4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide, 146986-50-7; enolase, 9014-08-8; fludarabine, 21679-14-1; glucose transporter 1, 172077-08-6; glyceraldehyde 3 phosphate dehydrogenase, 9001-50-7; ibrutinib, 936563-96-1; mitogen activated protein kinase 1, 137632-08-7; mitogen activated protein kinase 3, 137632-07-6; RhoA guanine nucleotide binding protein; RhoB guanine nucleotide binding protein; RhoC guanine nucleotide binding protein; ubiquitin protein ligase, 134549-57-8; vasculotropin, 127464-60-2 Funding details: GR-2009-1475467, GR-2011-02347441, GR-2011-02351370 Funding details: Fondazione CRT Funding details: Fondazione Cassa di Risparmio in Bologna Funding details: Cetacean Research Technology, CRT Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 21198, IG13119, IG15232, IG16985, IG17622, IG21408, IG2174, MCO-10007 Funding text 1: The authors would like to thank: Italian Association for Cancer Research (AIRC IG15232 and AIRC IG21408) (CR), (AIRC IG13119, AIRC IG16985, AIRC IG2174) (MM), (AIRC IG17622) (VGa), (AIRC 5x1000 project 21198, Metastatic disease: the key unmet need in oncology) (GG), (AIRC 5x1000 Special Programs MCO-10007 and 21198) (RF); Fondazione Neoplasie Sangue (Fo.Ne.Sa), Torino, Italy; University of Torino (local funds ex-60%) (MC); Ministero della Salute, Rome, Italy (Progetto Giovani Ricercatori GR-2011-02347441 [RB], GR-2009-1475467 [R.Bomben], and GR-2011-02351370 [MDB]). Fondazione Cassa di Risparmio di Torino (CRT) (VGr was recipient of a fellowship), Fondazione ?Angela Bossolasco? Torino, Italy (VGr was recipient of the ?Giorgio Bissolotti e Teresina Bosio? fellowship), the Italian Association for Cancer Research (AIRC, Ref 16343 VGr was recipient of the ?Anna Nappa? fellowship and MT is currently the recipient of a fellowship from AIRC Ref 19653). Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL) (CV was recipient of a fellowship). Pezcoller Foundation in collaboration with SIC (Societ? Italiana Cancerologia) (CV was a recipient of a {"}Fondazione Pezcoller - Ferruccio ed Elena Bernardi{"} fellowship). Funding text 2: The authors would like to thank: Italian Association for Cancer Research (AIRC IG15232 and AIRC IG21408) (CR), (AIRC IG13119, AIRC IG16985, AIRC IG2174) (MM), (AIRC IG17622) (VGa), (AIRC 5x1000 project 21198, Metastatic disease: the key unmet need in oncology) (GG), (AIRC 5x1000 Special Programs MCO-10007 and 21198) (RF); Fondazione Neoplasie Sangue (Fo.Ne.Sa), Torino, Italy; University of Torino (local funds ex-60%) (MC); Ministero della Salute, Rome, Italy (Progetto Giovani Ricercatori GR-2011-02347441 [RB], GR-2009-1475467 [R.Bomben], and GR-2011-02351370 [MDB]). Fondazione Cassa di Risparmio di Torino (CRT) (VGr was recipient of a fellowship), Fondazione “Angela Bossolasco” Torino, Italy (VGr was recipient of the “Giorgio Bissolotti e Teresina Bosio” fellowship), the Italian Association for Cancer Research (AIRC, Ref 16343 VGr was recipient of the “Anna Nappa” fellowship and MT is currently the recipient of a fellowship from AIRC Ref 19653). Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL) (CV was recipient of a fellowship). Pezcoller Foundation in collaboration with SIC (Societ{\`a} Italiana Cancerologia) (CV was a recipient of a {"}Fondazione Pezcoller - Ferruccio ed Elena Bernardi{"} fellowship).",
year = "2020",
doi = "10.3324/haematol.2019.217430",
language = "English",
volume = "105",
pages = "1042--1054",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "4",
}