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 MøllerPeter Nørgaard, N. Nora Bennani, Wee Joo Chng, Gaofeng Huang, Brian K. Link, Fabio Facchetti, James R. Cerhan, Francesco D’Amore, Stephen M. Ansell, Andrew L. Feldman

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although 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 bi-sulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22-rear-ranged ALCLs minimally expressed PD-L1 compared with 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.

Original languageEnglish (US)
Pages (from-to)1386-1398
Number of pages13
JournalBlood
Volume132
Issue number13
DOIs
StatePublished - Sep 27 2018
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Luchtel, R. A., Dasari, S., Oishi, N., Pedersen, M. B., Hu, G., Rech, K. L., Ketterling, R. P., Sidhu, J., Wang, X., Katoh, R., Dogan, A., Kip, N. S., Cunningham, J. M., Sun, Z., Baheti, S., Porcher, J. C., Said, J. W., Jiang, L., Hamilton-Dutoit, S. J., ... Feldman, A. L. (2018). Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood, 132(13), 1386-1398. https://doi.org/10.1182/blood-2018-03-838524