title: 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: Claude Bernard Lyon 1 University, CNRS UMR 5239 ENS - HCL, Lyon-Sud Medicine Faculty, Lyon, France.
authors: Wei W
authors: WW
authors: Chien
authors: Claude Bernard Lyon 1 University, CNRS UMR 5239 ENS - HCL, Lyon-Sud Medicine Faculty, Lyon, France.
authors: Régine
authors: R
authors: Catallo
authors: Claude Bernard Lyon 1 University, CNRS UMR 5239 ENS - HCL, Lyon-Sud Medicine Faculty, Lyon, France.
authors: Amel
authors: A
authors: Chebel
authors: Department of Hematology, CHU, Angers, France.
authors: Laurence
authors: L
authors: Baranger
authors: Department of Hematology, Hospices Civils de Lyon, Lyon, France.
authors: Xavier
authors: X
authors: Thomas
authors: Hematology Laboratory, CHU, Nantes, France.
authors: Marie-Christine
authors: MC
authors: Béné
authors: Department of Hematology, Hospices Civils de Lyon, Lyon, France.
authors: Luc M
authors: LM
authors: Gerland
authors: Department of Hematology, CHU, Angers, France.
authors: Aline
authors: A
authors: Schmidt
authors: Department of Hematology, St Louis Hospital, APHP, Paris, France.
authors: Kheira
authors: K
authors: Beldjord
authors: Department of Hematology, St Louis Hospital, APHP, Paris, France.
authors: Nathalie
authors: N
authors: Klein
authors: Department of Hematology, CHU, Rennes, France.
authors: Martine
authors: M
authors: Escoffre-Barbe
authors: Department of Hematology, CHU, Bordeaux, France.
authors: Thibaut
authors: T
authors: Leguay
authors: Department of Hematology, CHU, Toulouse, France.
authors: Françoise
authors: F
authors: Huguet
authors: Department of Hematology, CHU, Besançon, France.
authors: Fabrice
authors: F
authors: Larosa
authors: Department of Hematology, Hospices Civils de Lyon, Lyon, France.
authors: Sandrine
authors: S
authors: Hayette
authors: Department of Hematology, Hospices Civils de Lyon, Lyon, France.
authors: Adriana
authors: A
authors: Plesa
authors: Department of Hematology, CHU, Angers, France.
authors: Norbert
authors: N
authors: Ifrah
authors: Department of Hematology, St Louis Hospital, APHP, Paris, France.
authors: Hervé
authors: H
authors: Dombret
authors: Claude Bernard Lyon 1 University, CNRS UMR 5239 ENS - HCL, Lyon-Sud Medicine Faculty, Lyon, France; Department of Hematology, Hospices Civils de Lyon, Lyon, France.
authors: Gilles
authors: G
authors: Salles
authors: Department of Hematology, CHU, Angers, France.
authors: Agnès
authors: A
authors: Chassevent
authors: Claude Bernard Lyon 1 University, CNRS UMR 5239 ENS - HCL, Lyon-Sud Medicine Faculty, Lyon, France; Department of Hematology, Hospices Civils de Lyon, Lyon, France. Electronic address: martine.ffrench@chu-lyon.fr.
authors: Martine
authors: M
authors: Ffrench
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D020732:Cytogenetic Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016130:Immunophenotyping; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D019098:Telomerase / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; C509186:TERT protein, human; D019098:Telomerase
keywords: B-cell precursor-ALL; BCR-ABL1; Cell activation; IKAROS; Telomerase activity; p16(INK4A)/CDK4/pRb pathway