Abstract
Transcription deregulation resulting from genomic rearrangement is frequently observed in human lymphoid malignancies. For example, chromosomal aberrations, such as translocations or inversions, involving the immunoglobulin (Ig), T cell receptor (TCR) and the BCL11B loci, are expected to juxtapose the strong regulatory elements of these genes to the affected genes on the other chromosomes, resulting in such activation. Recently, ectopic activation of two orphan homeobox genes located ~2Mb apart on chromosome 5q35, HOX11L2/TLX3 and CSX1/NKX2-5 have been described, as a result of their fusion to BCL11B on chromosome 14q32 in acute lymphoblastic leukemia of T-lineage. Fusion of TLX3 to TCRδ has also been reported. We describe a novel translocation t(5;14)(q35;q11) identified in a case of B-cell chronic lymphoproliferative disorder. FISH and molecular studies located the chromosome 14 breakpoint within the TCRδgene, at the Dδ3 segment, and the chromosome 5 breakpoint 2.5kb downstream (telomeric) of the NKX2-5 gene. As a result of this translocation, both NKX2-5 and TLX3 were transcribed, whereas only NKX2-5 was detected at the protein level. To investigate the expression of these two genes in B-cell chronic proliferations, we screened 20 B-cell chronic lymphocytic leukemias (B-CLL) and 21 atypical B-CLL samples by RT-PCR and RQ-PCR. No sample demonstrated NKX2-5 expression and only one patient showed TLX3 expression. This patient had an evolutive B-CLL, with complex chromosomal abnormalities, without involvement of the band 5q35. In conclusion, this study identifies a new translocation involving a NK-like homeobox gene in a mature B lymphoproliferative disorder, underscoring precedent identification of NKX2-5 activation in two human lymphoid leukemia cell lines. It also demonstrates that deregulation of homeobox encoding genes is not a specific feature of acute leukemic proliferations, but is also observed in chronic malignancies.
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