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 this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy.


RESULTS
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
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.
Oncohematology Laboratory, Department of Pediatrics, University of Padova, Padova, Italy. benedetta.accordi@unipd.it
Benedetta
B
Accordi
Virginia
V
Espina
Marco
M
Giordan
Amy
A
VanMeter
Gloria
G
Milani
Luisa
L
Galla
Maria
M
Ruzzene
Manuela
M
Sciro
Luca
L
Trentin
Ruggero
R
De Maria
Geertruy
G
te Kronnie
Emanuel
E
Petricoin
Lance
L
Liotta
Giuseppe
G
Basso
D000263:Adenylate Kinase / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D040901:Proteomics; D015398:Signal Transduction
D009363:Neoplasm Proteins; D000263:Adenylate Kinase; D011241:Prednisone