Cargando…

Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL

BACKGROUND: In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In th...

Descripción completa

Detalles Bibliográficos
Autores principales: Accordi, Benedetta, Espina, Virginia, Giordan, Marco, VanMeter, Amy, Milani, Gloria, Galla, Luisa, Ruzzene, Maria, Sciro, Manuela, Trentin, Luca, De Maria, Ruggero, te Kronnie, Geertruy, Petricoin, Emanuel, Liotta, Lance, Basso, Giuseppe
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958847/
https://www.ncbi.nlm.nih.gov/pubmed/21042412
http://dx.doi.org/10.1371/journal.pone.0013552
_version_ 1782188381278568448
author Accordi, Benedetta
Espina, Virginia
Giordan, Marco
VanMeter, Amy
Milani, Gloria
Galla, Luisa
Ruzzene, Maria
Sciro, Manuela
Trentin, Luca
De Maria, Ruggero
te Kronnie, Geertruy
Petricoin, Emanuel
Liotta, Lance
Basso, Giuseppe
author_facet Accordi, Benedetta
Espina, Virginia
Giordan, Marco
VanMeter, Amy
Milani, Gloria
Galla, Luisa
Ruzzene, Maria
Sciro, Manuela
Trentin, Luca
De Maria, Ruggero
te Kronnie, Geertruy
Petricoin, Emanuel
Liotta, Lance
Basso, Giuseppe
author_sort Accordi, Benedetta
collection PubMed
description BACKGROUND: In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. METHODOLOGY/PRINCIPAL FINDINGS: We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could be considered as a new potential therapeutic target. Second, in patients with poor clinical response to prednisone we observed the up-modulation of LCK activity with respect to patients with good response. This tyrosine-kinase can be down-modulated with clinically used inhibitors, thus modulating LCK activity could be considered for further studies as a new additional therapy for prednisone-resistant patients. Further we also found an association between high levels of CYCLIN E and relapse incidence. Moreover, CYCLIN E is more expressed in early relapsed patients, who usually show an unfavourable prognosis. CONCLUSIONS/SIGNIFICANCE: We conclude that functional protein pathway activation mapping revealed specific deranged signalling networks in BCP-ALL that could be potentially modulated to produce a better clinical outcome for patients resistant to standard-of-care therapies.
format Text
id pubmed-2958847
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-29588472010-11-01 Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL Accordi, Benedetta Espina, Virginia Giordan, Marco VanMeter, Amy Milani, Gloria Galla, Luisa Ruzzene, Maria Sciro, Manuela Trentin, Luca De Maria, Ruggero te Kronnie, Geertruy Petricoin, Emanuel Liotta, Lance Basso, Giuseppe PLoS One Research Article BACKGROUND: In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. METHODOLOGY/PRINCIPAL FINDINGS: We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could be considered as a new potential therapeutic target. Second, in patients with poor clinical response to prednisone we observed the up-modulation of LCK activity with respect to patients with good response. This tyrosine-kinase can be down-modulated with clinically used inhibitors, thus modulating LCK activity could be considered for further studies as a new additional therapy for prednisone-resistant patients. Further we also found an association between high levels of CYCLIN E and relapse incidence. Moreover, CYCLIN E is more expressed in early relapsed patients, who usually show an unfavourable prognosis. CONCLUSIONS/SIGNIFICANCE: We conclude that functional protein pathway activation mapping revealed specific deranged signalling networks in BCP-ALL that could be potentially modulated to produce a better clinical outcome for patients resistant to standard-of-care therapies. Public Library of Science 2010-10-21 /pmc/articles/PMC2958847/ /pubmed/21042412 http://dx.doi.org/10.1371/journal.pone.0013552 Text en Accordi et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Accordi, Benedetta
Espina, Virginia
Giordan, Marco
VanMeter, Amy
Milani, Gloria
Galla, Luisa
Ruzzene, Maria
Sciro, Manuela
Trentin, Luca
De Maria, Ruggero
te Kronnie, Geertruy
Petricoin, Emanuel
Liotta, Lance
Basso, Giuseppe
Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL
title Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL
title_full Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL
title_fullStr Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL
title_full_unstemmed Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL
title_short Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL
title_sort functional protein network activation mapping reveals new potential molecular drug targets for poor prognosis pediatric bcp-all
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958847/
https://www.ncbi.nlm.nih.gov/pubmed/21042412
http://dx.doi.org/10.1371/journal.pone.0013552
work_keys_str_mv AT accordibenedetta functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT espinavirginia functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT giordanmarco functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT vanmeteramy functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT milanigloria functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT gallaluisa functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT ruzzenemaria functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT sciromanuela functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT trentinluca functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT demariaruggero functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT tekronniegeertruy functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT petricoinemanuel functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT liottalance functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall
AT bassogiuseppe functionalproteinnetworkactivationmappingrevealsnewpotentialmoleculardrugtargetsforpoorprognosispediatricbcpall