Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients

  • Background: Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed. Methods: We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients. Results: We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b. Conclusions: In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype.

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Author:Isabelle Bartram, Nicola Gökbuget, Cornelia Schlee, Sandra Heesch, Lars Fransecky, Stefan Schwartz, Reingard Stuhlmann, Kerstin Schäfer-Eckhart, Michael Starck, Albrecht Reichle, Dieter HoelzerGND, Claudia D. Baldus, Martin Neumann
URN:urn:nbn:de:hebis:30:3-347168
DOI:https://doi.org/10.1186/s13045-014-0051-y
ISSN:1756-8722
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/25023966
Parent Title (English):Journal of hematology & oncology
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2014/07/25
Date of first Publication:2014/07/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/07/25
Tag:Adult T-cell acute lymphoblastic leukemia; BCL11b; Expression; Mutation; Outcome; Standard risk
Volume:7
Issue:51
Page Number:10
First Page:1
Last Page:10
HeBIS-PPN:366011677
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0