Novel Fusion Transcripts Identified in Angioimmunoblastic T Cell Lymphoma
Shuangping Guo, Can Kucuk, Javeed Iqbal, Joseph Rohr, Chengfeng Bi, Chao Wang, Louis Staudt, Timothy McKeithan, Wing C Chan. University of Nebraska Medical Center, Omaha, NE; National Cancer Institute, NIH, Bethesda, MD
Background: Angioimmunoblastic T cell lymphoma (AITL) is the most common subtype of peripheral T-cell lymphoma. However, the molecular pathogenesis of AITL is not clear. Recurrent chromosomal rearrangements are important in tumorigenesis of nearly all types of hematolymphoid neoplasm but have not been described in AITL.
Design: We performed whole transcriptome sequencing in 22 cases of AITL.
Results: 2 novel fusion transcripts were found, one of them resulted from an intrachromosomal rearrangement involving CD28 and the Inducible T-cell Costimulator (ICOS) gene. The other one consisted of a fusion between Vav 1 Guanine Nucleotide Exchange Factor (VAV1) and Heterogeneous Nuclear Ribonucleoprotein M (HNRNPM) gene. Both of the fusion transcripts had been validated by Sanger sequencing. ICOS-CD28 fusion gene is comprised of exon 1 of ICOS gene encoding its signal peptide and exon 2-4 of CD28 gene encoding the intact mature CD28 protein. The structure of ICOS-CD28 indicated that the fusion gene was regulated by the ICOS promoter. Expression of ICOS and CD28 mRNA were evaluated in AITLs with and without ICOS-CD28 fusion gene. Mean scores (±SDs) for CD28 mRNA in AITLs with (n=1) and without (n=15) the fusion gene were 49.9 and 26.9±9.78. VAV1-HNRNPM fusion gene consisted of exon 1-25 of VAV1 gene and exon 3-16 of HNRNPM gene. VAV1 is identified as a proto-oncogene and highly expressed in hematologic malignancies, while HNRNPM influences pre-mRNA processing and metabolism. 68 amino acid residues in the C-terminal of VAV1 and 94 amino acid residues in the N-terminal of HNRNPM were deleted resulting in the loss of C-terminal Src homology 3 domain of VAV1 protein and the nuclear localization signal (NLS) of HNRNPM protein respectively, but most functional domains of both protein remained in VAV1-HNRNPM.
Conclusions: ICOS-CD28 may contribute to the tumorigenesis of AITL by altered CD28 express or cellular localization. The VAV1-HNRNPM fusion protein may have abnormal localization as well as altered function.
Tuesday, March 5, 2013 1:00 PM
Proffered Papers: Section G, Tuesday Afternoon