TY - JOUR
T1 - Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients
AU - Dufour, Annika
AU - Palermo, Giuseppe
AU - Zellmeier, Evelyn
AU - Mellert, Gudrun
AU - Duchateau-Nguyen, Guillemette
AU - Schneider, Stephanie
AU - Benthaus, Tobias
AU - Kakadia, Purvi M.
AU - Spiekermann, Karsten
AU - Hiddemann, Wolfgang
AU - Braess, Jan
AU - Truong, Sim
AU - Patten, Nancy
AU - Wu, Chung-Lin
AU - Lohmann, Sabine
AU - Dornan, David
AU - GuhaThakurta, Debraj
AU - Yeh, Ru Fang
AU - Salogub, Galina
AU - Solal-Celigny, Philippe
AU - Dmoszynska, Anna
AU - Robak, Tadeusz
AU - Montillo, Marco
AU - Catalano, John
AU - Geisler, Christian H.
AU - Weisser, Martin
AU - Bohlander, Stefan K.
PY - 2013/5/2
Y1 - 2013/5/2
N2 - In chronic lymphocytic leukemia (CLL) patients, disruptions of the TP53 tumor sup-pressor pathway by 17p13 deletion (del17p), somatic TP53 mutations, or down-regulation of microRNA-34a have been associated with a poor prognosis. So far, the impact of the various TP53 defects has not been evaluated in a large cohort of previously treated and relapsed CLL patients. Here, we present the results of TP53 gene sequencing and fluorescence in situ hybridization for del17p in a phase 3 clinical trial (REACH [Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia]). Of the 457 patients, 52 had TP53 mutations and 37 had del17p. In 24 (46%) of the TP53 mutated patients, no del17p was found and in 9 of the del17p patients, no TP53 mutation was identified. Based on a predicted proportion of TP53 disruption, a complete disruption of TP53 function, either by a combination of point mutations and/or del17p, was associated with a high risk for disease progression. Progressionfree survival of patients with a heterozygous TP53 mutation was not significantly different from patients with a completely intact TP53 locus. In addition, only a complete loss of TP53 function correlated with low microRNA-34a expression levels. This trial was registered at www.clinicaltrials.gov as #NCT00090051.
AB - In chronic lymphocytic leukemia (CLL) patients, disruptions of the TP53 tumor sup-pressor pathway by 17p13 deletion (del17p), somatic TP53 mutations, or down-regulation of microRNA-34a have been associated with a poor prognosis. So far, the impact of the various TP53 defects has not been evaluated in a large cohort of previously treated and relapsed CLL patients. Here, we present the results of TP53 gene sequencing and fluorescence in situ hybridization for del17p in a phase 3 clinical trial (REACH [Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia]). Of the 457 patients, 52 had TP53 mutations and 37 had del17p. In 24 (46%) of the TP53 mutated patients, no del17p was found and in 9 of the del17p patients, no TP53 mutation was identified. Based on a predicted proportion of TP53 disruption, a complete disruption of TP53 function, either by a combination of point mutations and/or del17p, was associated with a high risk for disease progression. Progressionfree survival of patients with a heterozygous TP53 mutation was not significantly different from patients with a completely intact TP53 locus. In addition, only a complete loss of TP53 function correlated with low microRNA-34a expression levels. This trial was registered at www.clinicaltrials.gov as #NCT00090051.
UR - http://www.scopus.com/inward/record.url?scp=84879724584&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-10-458695
DO - 10.1182/blood-2012-10-458695
M3 - Article
C2 - 23525797
AN - SCOPUS:84879724584
SN - 0006-4971
VL - 121
SP - 3650
EP - 3657
JO - Blood
JF - Blood
IS - 18
ER -