To provide fundamental insights into the leukemogenesis of adult T-cell leukemia/lymphoma (ATLL), we performed a molecular analysis of the chromosomal abnormalities in one ATLL case with a novel reciprocal translocation: t(2;14)(q34;q32). Using fluorescence in situ hybridization with cosmid probes derived from the 14q32 region, we characterized the rearranged 14q32 allele. Molecular cloning of the breakpoint revealed that the reciprocal translocation fused the 5' proximal region of the B-cell lymphoma 11B (BCL11B) gene segment (on 14q32) to the third intron of the HELIOS gene (on 2q34). Reverse transcription-polymerase chain reaction analysis of the leukemia cells revealed that a substantial level of the HELIOS-BCL11B fusion mRNA was expressed relative to the level of wild-type (WT)-BCL11B derived from the intact allele. In contrast, an aberrant HELIOS isoform was detected at a low level of expression compared to the expression of normal HELIOS isoforms. Functional analysis of the HELIOS-BCL11B fusion protein revealed reduced transcriptional suppression activity compared to that of the WT-BCL11B due to the loss of the N-terminal friend of GATA-repression motif, which functions as a metastasis-associated protein 2 binding site. We also found abnormal subnuclear localization of the ectopically expressed fusion protein compared to the localization of WT-BCL11B to subnuclear speckles in HEK293T cells. Our results suggest that dysfunction of the BCL11B gene plays an important role in the development of ATLL.
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