Identification of TYK2 translocations in cutaneous T-cell lymphoma–derived cell line and primary CD30 positive LPD patient samples. (A) Read support from RNA sequencing illustrating the forward fragment reads spanning the breakpoint between the 5′ NPM1 (NM_002520 c.1016) component and the 3′ TYK2 (NM_003331 c.2554) component and confirmation by Sanger sequencing. (B) Protein domain and exon diagram illustrating the preservation of N-terminal oligomerization and histone and DNA/RNA binding domains of NPM1 and the C-terminal pseudokinase (STY) and kinase domains of TYK2 in the NPM1-TYK2 fusion protein. (C) Cloning of the genomic breakpoint of the t(5;19) fusion event at chr5:170 832,813 and chr19:10 469,815 and confirmation by Sanger sequencing. (D) The NPM1-TYK2 fusion joins the positive strand of the NPM1 locus up to and including exon 9, with the inverted negative strand of the TYK2 locus between exons 15 and 16. (E) FISH studies. A TYK2 break-apart assay shows a TYK2 rearrangement in the MyLa cell line and in a primary cutaneous CD30-positive LPD (upper panel). NPM1-TYK2 fusion FISH reveals that NPM1 is the partner gene in both. A case that is negative for TYK2 translocation is also illustrated (lower panel).