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. 2019 May 14;133(26):2776–2789. doi: 10.1182/blood.2019000626

Figure 1.

Figure 1.

Recurrent MSCE116K mutations in ALK−ALCLs with DUSP22 rearrangements. (A) Sanger sequencing validated MSCE116K (chr8:72756068C>T) as shown (representative tracing from 3 independent samples). The mutation affected the conserved ERXR motif within the DNA binding domain of the bHLH transcription factor musculin. (B) Structural prediction of interaction between MSC (blue) and target DNA placed the mutated E116K residue (red) within the major groove. The model is superimposed on the TAL1:E2A experimental structure (gray) for comparison. (C) Data on 238 T-NHLs from exome sequencing and additional targeted resequencing of MSC identified MSCE116K exclusively in ALK− ALCLs, including systemic (ALCL, ALK−; frequency, 14.9%) and primary cutaneous (ALCL, cut.; 6.3%) types (P < .0001, cutaneous and systemic ALK− ALCLs vs all other subtypes, Fisher’s exact test,). Additional case details are given in supplemental Table 3. (D) Genetic subtyping of 160 ALCLs into ALK, DUSP22, TP63, and triple-negative (−/−/−) subtypes showed that MSCE116K was nearly exclusively associated with DUSP22 rearrangements (frequency, 35%; P < .0001, DUSP22 subtype vs all other subtypes, Fisher’s exact test). (E) ALK− ALCL with DUSP22 rearrangement and MSCE116K. Hematoxylin and eosin (H&E) stain shows sheets of large tumor cells (original magnification × 400). By immunohistochemistry, the tumor cells show strong and uniform staining for CD30 and musculin (nuclear staining pattern). See also supplemental Figure 4A. (F) Among WHO subtypes of T-NHL (N = 147), musculin protein expression was highest in systemic and cutaneous ALK− ALCLs. Data reflect the percentage of tumor cell nuclei positive for musculin by immunohistochemistry. Additional case details are given in supplemental Table 4. (G) Musculin expression was highest in ALCLs with DUSP22 rearrangements. The P value refers to differences among the 4 genetic subtypes.