Functional protein network activation mapping reveals new potential molecular drug targets for poor prognosis pediatric BCP-ALL

Benedetta Accordi, Virginia Espina, Marco Giordan, Amy van Meter, Gloria Milani, Luisa Galla, Maria Ruzzene, Manuela Sciro, Luca Trentin, Ruggero de Maria, Geertruy te Kronnie, Emanuel Petricoin, Lance Liotta, Giuseppe Basso

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numbere13552
JournalPLoS One
Volume5
Issue number10
DOIs
Publication statusPublished - 2010

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lymphocytic leukemia
Pediatrics
B-Lymphoid Precursor Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
prognosis
B-lymphocytes
Chemical activation
drugs
AMP-Activated Protein Kinases
Pharmaceutical Preparations
therapeutics
Prednisone
Proteins
proteins
prednisone
AMP-activated protein kinase
Signal transduction
Cell proliferation
Microarrays
Protein-Tyrosine Kinases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Functional protein network activation mapping reveals new potential molecular drug targets for poor prognosis pediatric BCP-ALL. / Accordi, Benedetta; Espina, Virginia; Giordan, Marco; van Meter, Amy; Milani, Gloria; Galla, Luisa; Ruzzene, Maria; Sciro, Manuela; Trentin, Luca; de Maria, Ruggero; te Kronnie, Geertruy; Petricoin, Emanuel; Liotta, Lance; Basso, Giuseppe.

In: PLoS One, Vol. 5, No. 10, e13552, 2010.

Research output: Contribution to journalArticle

Accordi, B, Espina, V, Giordan, M, van Meter, A, Milani, G, Galla, L, Ruzzene, M, Sciro, M, Trentin, L, de Maria, R, te Kronnie, G, Petricoin, E, Liotta, L & Basso, G 2010, 'Functional protein network activation mapping reveals new potential molecular drug targets for poor prognosis pediatric BCP-ALL', PLoS One, vol. 5, no. 10, e13552. https://doi.org/10.1371/journal.pone.0013552
Accordi, Benedetta ; Espina, Virginia ; Giordan, Marco ; van Meter, 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. In: PLoS One. 2010 ; Vol. 5, No. 10.
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AU - Galla, Luisa

AU - Ruzzene, Maria

AU - Sciro, Manuela

AU - Trentin, Luca

AU - de Maria, Ruggero

AU - te Kronnie, Geertruy

AU - Petricoin, Emanuel

AU - Liotta, Lance

AU - Basso, Giuseppe

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