Identification of IGHCδ–BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B‐cell lymphoma/leukemia

Abstract

In B-cell malignancies, genes implicated in B-cell differentiation, germinal center formation, apoptosis, and cell cycle regulation are juxtaposed to immunoglobulin loci through chromosomal translocations. In this study, we identified the BTB and CNC homology 2 (BACH2) gene as a novel translocation partner of the immunoglobulin heavy chain (IGH) locus in a patient with IGH-MYC-positive, highly aggressive B-cell lymphoma/leukemia carrying der(14)t(8;14) and del(6)(q15). Fluorescence in situ hybridization analysis using an IGH/MYC probe detected an IGH-MYC fusion signal on der(14) and IGH signal on del(6). Genome copy number analysis showed a deletion in the 6q15-25 region and a centromeric breakpoint within the BACH2 gene. cDNA bubble polymerase chain reaction using BACH2 primers revealed that the first exon of Cδ was fused to the 5'-untranslated region of BACH2 exon 2. The Cδ-BACH2 fusion transcript consisted of exon 1 of Cδ and exons 2 to 9 of BACH2, encompassing the entire BACH2 coding region, and the BACH2 was highly expressed in this patient. These results indicate that Cδ-BACH2 fusion may cause constitutive activation of BACH2. Although additional screening of 47 samples of B-cell non-Hodgkin's lymphoma (B-NHL) patients and 29 cell lines derived from B-cell malignancies by double-color fluorescence in situ hybridization analysis detected a split signal with deletion of centromeric region of BACH2 only in a patient with follicular lymphoma, BACH2 was highly expressed in lymphoma cells of the patient and B-NHL cell lines with IGH-MYC translocation. These findings suggest that BACH2 plays a critical role in B-cell lymphomagenesis, especially related to IGH-MYC translocation in some way.

A novel t(6;13)(q15;q34) translocation in a giant cell reparative granuloma (solid aneurysmal bone cyst)

“…A number of potential candidate genes are located in the chromosome 6q15 region, including BACH2 (BTB and CNC homolog 2), MAP3K7 (mitogen-activated protein kinase 7), GABRR1 (gamma-aminobutyric acid receptor, rho 1), GABRR2, RRAGD (Ras-related guanosine-5V-triphosphate [GTP]-binding D), and CAP8AP2 (caspase 8-associated protein 2). In an aggressive B-cell lymphoma, a cryptic chromosomal rearrangement of 14q32 with 6q15 generated an IGHCδ-BACH2 fusion transcript, which resulted in overexpression of BACH2 in the tumor [19]. Deletions of 6q15 have been observed in prostatic adenocarcinoma and pediatric T-lymphoblastic leukemia, which affect the MAP3K7 gene and the transforming growth factor β/PI3K-AKT pathways, respectively [20].…”

Specific HIV integration sites are linked to clonal expansion and persistence of infected cells

“…Both BACH2 and MKL2 are involved in the growth and development of cells, and BACH2 is known to play a key role in T-cell development ( 18 ). Both genes (and the MKL2 -related gene MKL1 , in which there were 4 independent integration sites, some of which were associated with clonally expanded cells in patient 1, Table S4) have been implicated in human cancers ( 19 – 21 ), where they were activated by DNA rearrangements that created gene fusions. The pattern of multiple integrations in MKL2 and BACH2 found in the patients cannot be the result of preferential integration because HIV integration is neither intron specific nor orientation specific ( 22 ).…”

Reservoir expansion by T-cell proliferation may be another barrier to curing HIV infection

“…The authors found that in all five patients there was evidence of clonal expansion of HIV-1-infected cells. One patient in particular (patient 1) presented another very interesting result: two genes, for the transcription factors MKL2 and BACH2, which are associated with cell growth and have been linked to human cancers (18,19), showed a disproportionately large number of integration sites. This was surprising because, given the general randomness of integration site selection, one would not expect to find any marked imbalance in the genomic distribution of proviruses in populations of infected cells.…”