Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trial.
The prognosis of fludarabine (F)-refractory chronic lymphocytic leukemia (CLL) is very poor, and underlying mechanisms are only partly understood. To assess the contribution of p53 abnormalities to F-refractory CLL, we studied TP53 mutations in the CLL2H trial (subcutaneous alemtuzumab; n = 99). We found TP53 mutations in 37% of patients. Twelve of 67 (18%) patients without the 17p deletion showed a TP53 mutation and 50% showed evidence of uniparental disomy. A total of 75% of cases with TP53 mutation (without 17p-) showed clonal evolution/expansion. TP53 mutations had no impact on overall survival (P = .48). CLL with the 17p deletion or TP53 mutation showed very low miR-34a expression. To investigate the mechanisms underlying refractory CLL beyond p53, we studied cases without 17p-/TP53 mutation in detail. In several paired samples before and after F-refractory disease, no change in p21/p53 induction was observed after DNA damage. Although TP53 mutations and 17p deletions are found in a high proportion of F-refractory CLL, more than half of the cases cannot be explained by p53 defects (deletion or mutation), and alternative mechanisms need to be investigated. Alemtuzumab is effective irrespective of genetic high-risk subgroups with TP53 mutations. These clinical trials are registered at www.clinicaltrials.gov as #NCT00274976.
Zenz
Thorsten
T
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Häbe
Sonja
S
Denzel
Tina
T
Mohr
Julia
J
Winkler
Dirk
D
Bühler
Andreas
A
Sarno
Antonio
A
Groner
Silja
S
Mertens
Daniel
D
Busch
Raymonde
R
Hallek
Michael
M
Döhner
Hartmut
H
Stilgenbauer
Stephan
S
D000279:Administration, Cutaneous; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005500:Follow-Up Studies; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D017211:Treatment Failure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine