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

V. Griggio, C. Vitale, M. Todaro, C. Riganti, J. Kopecka, C. Salvetti, R. Bomben, M.D. Bo, D. Magliulo, D. Rossi, G. Pozzato, L. Bonello, M. Marchetti, P. Omedè, A.A. Kodipad, L. Laurenti, G.D. Poeta, F.R. Mauro, R. Bernardi, T. ZenzV. Gattei, G. Gaidano, R. Foà, M. Massaia, M. Boccadoro, M. Coscia

Research output: Contribution to journalArticlepeer-review

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. ©2020 Ferrata Storti Foundation
Original languageEnglish
Pages (from-to)1042-1054
Number of pages13
JournalHaematologica
Volume105
Issue number4
DOIs
Publication statusPublished - 2020

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

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