Abstract
BackgroundRisk 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.MethodsWe 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.ResultsWe 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.ConclusionsIn 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.
Highlights
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
BCL11b is heterogeneously expressed in adult T-ALL BCL11b mRNA expression levels were not detectable in CD34 positive hematopoietic progenitor cells or unselected bone marrow (BM) samples from healthy donors, whereas high expression levels were found in CD3 positive mature T-cells
BCL11b associated global gene expression profile To explore the underlying transcriptional profile associated with aberrant BCL11b expression in T-ALL, we analyzed microarray expression data of an independent cohort of 86 adult T-ALL patients [33]
Summary
Patients We analyzed diagnostic BM material of 195 adult T-ALL patients sent to the GMALL reference laboratory [48]. Immunophenotyping of the samples was centrally performed in the GMALL reference laboratory at the Charité, University Hospital Berlin, Germany, as previously described [49,50], and classified into the T-ALL subgroups: early (n = 50), mature (n = 33) and thymic (n = 112). Gene expression profiles BCL11b-associated GEP of an independent set of 86 adult T-ALL samples were generated from raw data obtained from the Microarrays Innovations in Leukemia (MILE) multicenter study (HG-U133 Plus 2.0; Affymetrix, Santa Clara, CA, USA) [33]. For the GEP-analysis, samples were divided into quartiles (Q) according to BCL11b expression [median of the two probe sets (219528_s_at, 222895_s_at)]. Kaplan–Meier analysis of overall survival (OS) in T-ALL with respect to BCL11b mRNA expression. Molecular characteristics of thymic GMALL T-ALL patients in respect to BCL11b expression. NG supervised the GMALL study center, performed statistical analysis and reviewed the manuscript. Hamburg, Germany. 4Department of Hematology and Oncology, Klinikum Nürnberg, Nürnberg, Germany. 5Department of Hematology and Oncology, Klinikum Schwabing, München, Germany. 6Department for Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
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