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Cytogenetic characterization of triple-hit B-cell lymphoma cell line SC-1 reveales novel chromosomal aberration t(14;17)(q32;q21) activating HOXB5 and miR10a.

ABSTRACT: BCL2, BCL6 and MYC represent major oncogenes in B-cell lymphoma. They are activated via chromosomal translocations juxtaposing IGH to BCL2 and MYC, and by fusion of diverse partner genes with BCL6. So called double-hit lymphomas carry BCL2 and MYC rearrangements while triple-hit lymphomas contain additionally BCL6-fusions. These translocations are of diagnostic importance and associated with poor prognosis. Here, we cytogenetically and genomically characterized triple-hit B-cell lymphoma cell line SC-1 which carries t(14;18)(q32;q21) targeting IGH and BCL2, t(8;14)(q24;q32) juxtaposing IGH and MYC, and t(3;3)(q25;q27) fusing MBNL1 and BCL6. In addition, we detected a novel chromosomal rearrangement, t(14;17)(q32;q21), which was mapped by FISH and analyzed by gene expression profiling. This translocation juxtaposed IGH with the HOXB gene cluster at 17q21, resulting in aberrant activation of homeobox gene HOXB5 and micro-RNA gene miR10a. HOXB5 expression was additionally supported by hematopoietic stem cell factor ZNF521. Functional examinations revealed that HOXB5 inhibited the apoptotic driver BCL2L11 and mediated survival in the presence of etoposide. MiR10a inhibited BCL6 and may thus play a role in later stages of lymphomagenesis. Taken together, we identified HOXB5 and miR10a as novel oncogenes in triple-hit B-cell lymphoma and established cell line SC-1 as a suitable model for their examination.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST1073 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:The poor outcome of high-grade B-cell lymphoma, with rearrangements of MYC, BCL2 and/or BCL6, also known as double-hit lymphoma or triple-hit lymphoma (DHL or THL), has been well documented, while the clinical significance of extra copies of MYC, BCL2 or BCL6 are still less well known. METHODS:In total, 130 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) were included in our study. Fluorescence in situ hybridization and immunohistochemistry were performed in all cases to evaluate the genetic status and protein expression levels of MYC, BCL2 and BCL6. RESULTS:Among the 130 cases of DLBCL, the prevalence rates of extra copies of MYC, BCL2 and BCL6 were 10.8, 20.0 and 14.6%, respectively, and the corresponding rates of gene rearrangement were 10.0, 14.6 and 16.9%, respectively. In total, 7.7% (10/130) of patients were DHL/THL; 9.2% (12/130) of patients were DLBCL with MYC and BCL2 and/or BCL6 gene abnormalities including rearrangements or extra copies, while excluded DHL/THL. The positive protein expression rates of MYC, BCL2 and BCL6 were 46.9% (61), 75.4% (98) and 70.0% (91), respectively. Among the 51 cases with MYC/BCL2 co-expression, 14 cases showed concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities, and the remaining 37 cases were classified as double-expressor lymphoma (DEL). MYC and BCL2 rearrangement and BCL2 extra copies were all associated with upregulated protein expression. Cases with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities were both associated with MYC/BCL2 co-expression. Patients with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities excluded DHL/THL had shorter OS (P?<?0.001) than patients with DLBCL with no genetic change, and showed no statistical different with patients with DHL/THL (P?=?0.419). Extra copies of MYC was independent prognostic factors for DLBCL. CONCLUSIONS:Patients with MYC and BCL2 and/or BCL6 gene extra copies might show a trend towards poor prognosis, and the detection of extra copies of MYC, BCL2 and BCL6 might deserve more attention.

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Cytogenetic characterization of triple-hit B-cell lymphoma cell line SC-1 reveales novel chromosomal aberration t(14;17)(q32;q21) activating HOXB5 and miR10a.

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