Abstract
Original language | English |
---|---|
Pages (from-to) | 1042-1054 |
Number of pages | 13 |
Journal | Haematologica |
Volume | 105 |
Issue number | 4 |
DOIs | |
Publication status | Published - 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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HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia. / Griggio, V.; Vitale, C.; Todaro, M. et al.
In: Haematologica, Vol. 105, No. 4, 2020, p. 1042-1054.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia
AU - Griggio, V.
AU - Vitale, C.
AU - Todaro, M.
AU - Riganti, C.
AU - Kopecka, J.
AU - Salvetti, C.
AU - Bomben, R.
AU - Dal Bo, Michele
AU - Magliulo, D.
AU - Rossi, D.
AU - Pozzato, G.
AU - Bonello, L.
AU - Marchetti, M.
AU - Omedè, P.
AU - Kodipad, A.A.
AU - Laurenti, L.
AU - Poeta, G.D.
AU - Mauro, F.R.
AU - Bernardi, R.
AU - Zenz, T.
AU - Gattei, V.
AU - Gaidano, G.
AU - Foà, R.
AU - Massaia, M.
AU - Boccadoro, M.
AU - Coscia, M.
N1 - Cited By :8 Export Date: 17 February 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 (Società Italiana Cancerologia) (CV was a recipient of a "Fondazione Pezcoller - Ferruccio ed Elena Bernardi" fellowship). 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PY - 2020
Y1 - 2020
N2 - 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
AB - 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
KW - 2 (2 amino 3 methoxyphenyl)chromone
KW - 2 morpholino 8 phenylchromone
KW - 4 (1 aminoethyl) n (4 pyridyl)cyclohexanecarboxamide
KW - actin
KW - CD19 antigen
KW - enolase
KW - enolase 1
KW - fludarabine
KW - glucose transporter 1
KW - glyceraldehyde 3 phosphate dehydrogenase
KW - hypoxia inducible factor 1alpha
KW - ibrutinib
KW - messenger RNA
KW - mitogen activated protein kinase 1
KW - mitogen activated protein kinase 3
KW - protein p53
KW - RhoA guanine nucleotide binding protein
KW - ubiquitin protein ligase
KW - unclassified drug
KW - vasculotropin
KW - von Hippel Lindau protein
KW - animal cell
KW - animal experiment
KW - animal model
KW - animal tissue
KW - antineoplastic activity
KW - apoptosis
KW - Article
KW - blood sampling
KW - Burkitt lymphoma
KW - cell activation
KW - cell culture
KW - cell death
KW - cell isolation
KW - cell viability assay
KW - chronic lymphatic leukemia
KW - comparative study
KW - controlled study
KW - cytosolic fraction
KW - cytotoxicity
KW - down regulation
KW - gene expression
KW - gene expression regulation
KW - gene mutation
KW - gene repression
KW - gene set enrichment analysis
KW - genetic analysis
KW - genetic transcription
KW - human
KW - immuno enzymatic measurement
KW - leukemia cell line
KW - lymphatic leukemia
KW - major clinical study
KW - nonhuman
KW - nuclear expression
KW - oncogene c H ras
KW - Pi3K/Akt signaling
KW - protein degradation
KW - real time polymerase chain reaction
KW - signal transduction
KW - stroma cell
KW - survival factor
KW - tumor microenvironment
KW - upregulation
KW - Western blotting
U2 - 10.3324/haematol.2019.217430
DO - 10.3324/haematol.2019.217430
M3 - Article
VL - 105
SP - 1042
EP - 1054
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 4
ER -