title: Low expression of T-cell transcription factor BCL11b predicts inferior survival in adult standard risk T-cell acute lymphoblastic leukemia patients.
abstract: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bartram
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlee
authors.forename: Sandra
authors.initials: S
authors.lastname: Heesch
authors.forename: Lars
authors.initials: L
authors.lastname: Fransecky
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwartz
authors.forename: Reingard
authors.initials: R
authors.lastname: Stuhlmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schäfer-Eckhart
authors.forename: Michael
authors.initials: M
authors.lastname: Starck
authors.forename: Albrecht
authors.initials: A
authors.lastname: Reichle
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
authors.affiliation: Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, 12203, Germany. martin.neumann@charite.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D012307:Risk Factors; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C479740:BCL11B protein, human; D014408:Biomarkers, Tumor; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins