Identification of a new subclass of ALK negative ALCL expressing aberrant levels of ERBB4 transcripts

Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including ALK positive and ALK negative systemic forms. To discover biomarkers and/or genes involved in ALK negative ALCL pathogenesis, we applied the Cancer Outlier Profile Analysis (COPA) algorithm to a gene expression profiling data set including 249 cases of T-NHLs and normal T-cells. Ectopic co-expression of ERBB4 and COL29A1 genes was detected in 24% of ALK negative ALCL patients. RNA sequencing and 5'RNA Ligase Mediated Rapid Amplification of cDNA Ends (RLM-RACE) identified two novel ERBB4 truncated transcripts, displaying intronic Transcription Starting Sites. ERBB4 expression was confirmed at protein level by western blotting and immunohistochemistry. Moreover, by luciferase assays we defined that the expression of ERBB4 aberrant transcripts is promoted by endogenous intronic Long Terminal Repeats (LTRs). In conclusion, we identified a new subclass of ALK negative ALCL characterized by aberrant expression of ERBB4 truncated transcripts carrying intronic 5'UTRs. To discover genes putatively involved in the pathogenesis of ALK negative ALCL patients, we applied the Cancer Outlier Profile Analysis (COPA) algorithm10 to a large gene expression profiling (GEP) data set including 249 cases of T-NHLs and normal T-cells, obtained as previously described (PMID: 22740451 http://www.ncbi.nlm.nih.gov/pubmed/22740451).