Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract with STAT3-JAK2 fusion. (A-B) Duodenal biopsy shows a monotonous population of small lymphocytes in the lamina propria with preservation of the glands (hematoxylin and eosin stain; patient 2; original magnification ×40 [A] and ×400 [B]). By immunohistochemistry, the cells are positive for (C) CD3 and (D) CD4 and negative for (E) CD8 (original magnification ×400 [C-E]). (F) FISH using a break-apart probe to the JAK2 gene region shows separations of red and green signals, indicating the presence of a rearrangement (original magnification ×600). (G) FISH using a dual-fusion probe for the STAT3 (red) and JAK2 (green) gene regions shows red-green fusion signals (f), indicating the presence of fusion of these 2 regions (original magnification ×600). (H) RNA sequencing identifies chimeric reads supporting the presence of STAT3-JAK2 fusion joining the end of exon 23 of STAT3 with the beginning of exon 17 of JAK2. The identical breakpoint was found in all 3 patients who had GI TLPD with STAT3-JAK2 fusion whose samples were successfully sequenced. (I) Sanger sequencing confirms the STAT3-JAK2 breakpoint identified by RNA sequencing. (J) Protein domain structure of STAT3, JAK2, and predicted STAT3-JAK2 fusion protein. The amino acid numbers at the breakpoints are shown as well as the location of STAT3^Y705. Using immunohistochemistry showed that the cells lack staining for (K) pSTAT3^Y705 but are positive for (L) pSTAT5^Y694 (patient 2; original magnification ×1000). CCD, coiled coil domain; DBD, DNA binding domain; FERM, four-point-one, ezrin, radixin, moesin homology domain; JH1, JAK homology 1 (tyrosine kinase) domain; JH2, JAK homology 2 (pseudokinase) domain; LD, linker domain; NTD, N-terminal domain; SH2, Src homology 2 domain; TAD, transcription activation domain.