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Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements

Rebecca A. Luchtel, Surendra Dasari, Naoki Oishi, Martin Bjerregård Pedersen, Guangzhen Hu, Karen L. Rech, Rhett P. Ketterling, Jagmohan Sidhu, Xueju Wang, Ryohei Katoh, Ahmet Dogan, N. Sertac Kip, Julie M. Cunningham, Zhifu Sun, Saurabh Baheti, Julie C. Porcher, Jonathan W. Said, Liuyan Jiang, Stephen Jacques Hamilton-Dutoit, Michael Boe Møller, Peter Nørgaard, N. Nora Bennani, Wee-Joo Chng, Gaofeng Huang, Brian K. Link, Fabio Facchetti, James R. Cerhan, Francesco d'Amore, Stephen M. Ansell and Andrew L. Feldman

Key points

  • DUSP22-rearranged anaplastic large cell lymphomas (ALCLs) belong to a distinct subset of ALCLs lacking activated STAT3.

  • DUSP22-rearranged ALCLs have a unique molecular signature characterized by DNA hypomethylation and an immunogenic phenotype.

Abstract

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. While ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. Additionally, DUSP22-rearranged ALCLs minimally expressed PD-L1 compared to other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like, immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.

  • Submitted March 8, 2018.
  • Accepted July 28, 2018.