Identification of Novel Fusion Genes with 28S Ribosomal DNA in Hematologic Malignancies

Abstract 4418

Chromosomal translocations play a crucial role in tumorigenesis, often resulting in the formation of chimeric genes or in gene deregulation through position effects. Hematologic malignancies are associated with a large number of such rearrangements. In this study, we have identified 28S ribosomal DNA (RN28S1) gene as a novel fusion partner of the B-cell leukemia/lymphoma 11B (BCL11B), immunoglobulin kappa variable 3–20(IGKV3–20), and component of oligomeric golgi complex 1 (COG1) locus in T-cell acute lymphoblastic leukemia (T-ALL), Burkitt lymphoma (BL) and multiple myeloma (MM), respectively.

RN28S1-BCL11B fusion gene was identified in T-ALL with t(6;14)(q25;q32) by cDNA bubble PCR using BCL11B primers, whereas the breakpoint of 14q32 was near, but out of, the BCL11B. BLAST search revealed that the RN28S1 was fused to BCL11B within exon3 (coding region). During the expression analysis of RN28S1-BCL11B, We identified the same type of RN28S1-BCL11B fusion transcripts in a BL and 2 MM cell lines, and unexpectedly identified other RN28S1-fusion transcripts in hematologic malignancy cell lines. Fusion of RN28S1 and IGKV3–20 exon2 (coding region) was detected in 2 BL and a MM cell lines, and that of RN28S1 and COG1 within exon 13 (coding region) in a MM cell line. Furthermore, RN28S1 breakpoint was concentrated in between 1.4∼1.8kb.

RN28S1 is located in the p12 region of chromosomes 13, 14, 15, 21 and 22. The ribosomal RNA (rDNA) gene repeats are essential housekeeping genes found in all organisms. A gene amplification system maintains large clusters of tandemly repeated copies in the chromosome, and as the product, ribosomal RNA accounts for ∼70% of total RNA in the cell.

rDNA exists in high copy number in most eukaryotic cells. Repeatitive genes tend to lose copies through homologous recombination among the repeats. The rDNA has a gene amplification system, thought to be present in most eukaryotes, that function to keep high copy numbers. In the tumor cells, rDNA is transcribed higher than normal cells for cell proliferation. Thus, that may be associated with chromosome instability.

RN28S1 degradation was reported to be associated with apoptosis of hematologic malignancies, and previously, another group was detected RN28S1-BCL6 fusion genes in gastric lymphoma. This case was no expression of BCL6 protein. In conclusion, these results suggest that RN28S1 fusions are concerned with the play something role of tumorigenesis. Because of RN28S1 fused to BCL11B, IGKV3–20 and COG1 whose breakpoints were involved in the coding region, we speculate that these fusion genes are not produce normal structure.