Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is associated with chromosomal aberrations characterized by juxtaposition of proto-oncogenes to T-cell receptor gene loci (TCR), resulting in the deregulated transcription of these proto-oncogenes. Here, we describe the molecular characterization of a novel chromosomal aberration, inv(14)(q11.2q32.31), in a T-ALL sample, involving the recently described BCL11B gene and the TCRD locus. The inversion joined the 5 0 part of BCL11B, including exons 1-3, to the TRDD3 gene segment of the TCRD locus, whereas the reciprocal breakpoint fused the TRDV1 gene segment to the fourth exon of BCL11B. The TRDV1-BCL11B joining region was 1344 bp long and contained fragments derived from 20q11.22, 3p21.33 and from 11p12, indicating the complex character of this aberration. A strong expression of inframe transcripts with truncated BCL11B and TCRD constant region (TRDC) were observed, but in contrast to normal T cells and other T-ALL samples, no wild-type BCL11B transcripts were detected in the T-ALL sample. Screening of 37 other T-ALLs revealed one additional case with expression of the BCL11B-TRDC fusion transcript. As BCL11B appears to play a key role in T-cell differentiation, BCL11B disruption and disturbed expression may contribute to the development of T-cell malignancies in man.

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells

“…In keeping with the idea that Bcl11b might act as a tumor suppressor, we recently reported a T-ALL case Inhibition of BCL11B leads to apoptosis P Grabarczyk et al carrying an inversion involving the BCL11B locus, which abolished the expression of the wild-type gene (Przybylski et al, 2005). However, our data indicate that this is a rare event in T-ALL.…”

“…In mice, deletions within BCL11B were found in normal thymocytes and in irradiation-induced lymphomas (Wakabayashi et al, 2003a;Sakata et al, 2004). We and others reported high levels of BCL11B mRNA expression in the majority of T-ALL and T-cell leukemia/lymphoma cell lines Przybylski et al, 2005). Furthermore, BCL11B overexpression was found in the acute type of ATLL in contrast to no or low expression of the gene in the lymphoma type (Oshiro et al, 2006).…”

“…Quantification of BCL11B mRNA was performed as described elsewhere (Przybylski et al, 2005). BCLxL TRAIL and b-2-microglobulin (b-2-MG) reference gene mRNA expression was measured with the 7500 RealTime PCR System (Applied Biosystems, Foster City, CA, USA) using the Platinum SYBR Green qPCR SuperMix-uracil-DNA glycosylase (Invitrogen) according to the manufacturer's instructions.…”

“…The translocation t(14:14)(q11.2; q32.31) or the inversion inv(14)(q11.2q32.31) disrupting the BCL11B locus were found in one adult T-cell leukemia/lymphoma (ATLL) case and in two cases of Tcell acute lymphoblastic leukemias (T-ALL), respectively (Gesk et al, 2003;Przybylski et al, 2005). Further translocations involving the BCL11B locus were reported in three T-ALL-derived cell lines and in one case of acute myelocytic leukemia Nagel et al, 2003;Bezrookove et al, 2004).…”

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

“…Identification of TCRD-LMO2 breakpoint regions was performed by long-range ligation-mediated PCR as previously described. 16 Notch1 mutations were identified by screening the heterodimerization and PEST domains. 17 For this study only mutations with deletions and insertions were selected based on the likelihood of providing a highly specific molecular target for a sensitive PCR approach.…”