Identification of novel fusion genes with 28S ribosomal DNA in hematologic malignancies

Abstract

Fusion genes are frequently observed in hematologic malignancies and soft tissue sarcomas, and are usually associated with chromosome abnormalities. Many of these fusion genes create in-frame fusion transcripts that result in the production of fusion proteins, and some of which aid tumorigenesis. These fusion proteins are often associated with disease phenotype and clinical outcome, and act as markers for minimal residual disease and indicators of therapeutic targets. Here, we identified the 28S ribosomal DNA (RN28S1) gene as a novel fusion partner of the B-cell leukemia/lymphoma 11B gene (BCL11B), the immunoglobulin κ variable 3-20 gene (IGKV3-20) and the component of oligomeric Golgi complex 1 gene (COG1) in hematologic malignancies. The RN28S1-BCL11B fusion transcript was identified in a case with mixed-lineage (T/myeloid) acute leukemia having t(6;14)(q25;q32) by cDNA bubble PCR using BCL11B primers; however, the gene fused to BCL11B on 14q32 was not on 6q25. IGKV3-20-RN28S1 and COG1-RN28S1 fusion transcripts were identified in the Burkitt lymphoma cell line HBL-5, and the multiple myeloma cell line KMS-18. RN28S1 would not translate, and the breakpoints in partner genes of RN28S1 were within the coding exons, suggesting that disruption of fusion partners by fusion to RN28S1 is the possible mechanism of tumorigenesis. Although further analysis is needed to elucidate the mechanism(s) through which these RN28S1-related fusions play roles in tumorigenesis, our findings provide important insights into the role of rDNA function in human genomic architecture and tumorigenesis.

Novel ZEB2-BCL11B Fusion Gene Identified by RNA-Sequencing in Acute Myeloid Leukemia with t(2;14)(q22;q32)

“…The fusion genes BCL11B-TLX3 , BCL11B-NKX2-5 , BCL11B-TRD , and IKZF2-BCL11B have all been reported in T-cell acute lymphoblastic leukemia [ 24 ]. An RN28S1-BCL11B fusion transcript was also identified in a case of mixed-lineage (T/myeloid) acute leukemia with t(6;14)(q25;q32) [ 25 ]. The RN28S1 gene is not translated to protein and BCL11B and RN28S1 were fused in opposite transcription directions.…”

“…The RN28S1 gene is not translated to protein and BCL11B and RN28S1 were fused in opposite transcription directions. Thus, disruption of the normal functions of BCL11B seemed to contribute to leukemogenesis in this case [ 25 ]. BCL11B was also involved in a case of AML with a similar chromosomal aberration, a t(6;14)(q25~q26;q32), but there was not enough material to identify the partner genomic locus [ 26 ].…”

Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance

“…We modified the original bubble PCR method for the cloning of unknown DCC transcripts, as described previously (Chinen et al, ; Kobayashi et al, ). Nested PCR was performed using primers NVAMP‐1 (bubble oligo) and DCC‐2A‐1 (exon 2) for first round PCR, and NVAMP‐2 (bubble oligo) and DCC‐2A‐2 (exon 2) for nested PCR.…”

An adult case of biphenotypic acute leukemia with t(6;14)(q25;q32)

“…The partner gene of this translocation is unknown. The 28S ribosomal DNA (RN28S1) was reported as a candidate fusion partner (Kobayashi et al,2014), but this gene is not located in 6q25. The phenotype of haematological malignancies with t(6;14)(q25;q32) is variable.…”

“…The phenotype of haematological malignancies with t(6;14)(q25;q32) is variable. These include acute lymphoblastic leukemia (ALL) (Heerema et al,2002), mixed phenotype acute leukemia (Hayashi et al,1990, Batanian et al,1996, Georgy et al,2008, Kobayashi et al,2014, acute myeloid leukaemia (AML) (Raimondi et al,1989, Bezrookove et al,2004, chronic T cell neoplasm (Inwards et al,1990) and chronic lymphocytic leukaemia (CLL) (Mayr et al,2006). In 7 of 9 acute leukaemia cases with this translocation, both myeloid and T-cell lineage markers were detected.…”