The p16(INK4A)/pRb pathway and telomerase activity define a subgroup of Ph+ adult Acute Lymphoblastic Leukemia associated with inferior outcome.

Abstract

Adult Acute Lymphoblastic Leukemia (ALL) therapies have been improved by pediatric-like approaches. However, treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials. The p16(INK4A)/CDK4-6/pRb pathway and telomerase activity, which are implicated in cell activation and aging, were analyzed to identify new prognostic markers. Proteins of the p16(INK4A)/CDK4-6/pRb pathway and telomerase activity were analyzed in 123 adult B-cell precursor (BCP) ALL cases included in the GRAALL/GRAAPH trials. We found a significantly increased expression of p16(INK4A) in BCP-ALLs with MLL rearrangement. Telomerase activity was significantly lower in Philadelphia chromosome-negative/IKAROS-deleted (BCR-ABL1(-)/IKAROS(del)) cases compared to Philadelphia chromosome-positive (BCR-ABL1+) BCP-ALLs. In BCR-ABL1+ ALLs, high CDK4 expression, phosphorylated pRb (p-pRb) and telomerase activity were significantly associated with a shorter disease-free survival (DFS) and event-free survival (EFS). Enhanced p16(INK4A) expression was only related to a significantly shorter DFS. In vitro analyses of normal stimulated lymphocytes after short- and long-term cultures demonstrated that the observed protein variations of poor prognosis in BCR-ABL1+ ALLs may be related to cell activation but not to cell aging. For these patients, our findings argue for the development of therapeutic strategies including the addition of new lymphocyte activation inhibitors to current treatments.

• Authors: Wei W Chien, Régine Catallo, Amel Chebel, Laurence Baranger, Xavier Thomas, Marie-Christine Béné, Luc M Gerland, Aline Schmidt, Kheira Beldjord, Nathalie Klein, Martine Escoffre-Barbe, Thibaut Leguay, Françoise Huguet, Fabrice Larosa, Sandrine Hayette, Adriana Plesa, Norbert Ifrah, Hervé Dombret, Gilles Salles, Agnès Chassevent, Martine Ffrench
• Journal: Leukemia research (Leuk Res) Vol. 39 Issue 4 Pg. 453-61 (Apr 2015) ISSN: 1873-5835 [Electronic] England
• PMID: 25675863 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Cyclin-Dependent Kinase Inhibitor p16
• RNA, Messenger
• Retinoblastoma Protein
• TERT protein, human
• Telomerase

Topics

• Adolescent
• Adult
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Blotting, Western
• Case-Control Studies
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Cytogenetic Analysis
• Female
• Follow-Up Studies
• Humans
• Immunophenotyping
• Lymphocytes (metabolism)
• Male
• Middle Aged
• Neoplasm Staging
• Philadelphia Chromosome
• Phosphorylation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, mortality, pathology)
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Retinoblastoma Protein (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Telomerase (metabolism)
• Young Adult