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

Autor:	Luchtel RA; Department of Laboratory Medicine and Pathology and., Dasari S; Department of Health Sciences Research, Mayo Clinic, Rochester, MN., Oishi N; Department of Laboratory Medicine and Pathology and.; Department of Pathology, University of Yamanashi, Chuo, Yamanashi, Japan., Pedersen MB; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark., Hu G; Department of Laboratory Medicine and Pathology and., Rech KL; Department of Laboratory Medicine and Pathology and., Ketterling RP; Department of Laboratory Medicine and Pathology and., Sidhu J; Department of Pathology and Laboratory Medicine, United Health Services Hospitals, Johnson City/Binghamton, NY., Wang X; Department of Pathology, China-Japan Union Hospital of Jilin University, Changchun, China., Katoh R; Department of Pathology, University of Yamanashi, Chuo, Yamanashi, Japan., Dogan A; Department of Laboratory Medicine and Pathology and., Kip NS; Department of Laboratory Medicine and Pathology and., Cunningham JM; Department of Laboratory Medicine and Pathology and., Sun Z; Department of Health Sciences Research, Mayo Clinic, Rochester, MN., Baheti S; Department of Health Sciences Research, Mayo Clinic, Rochester, MN., Porcher JC; Division of Hematology, Mayo Clinic, Rochester, MN., Said JW; Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA., Jiang L; Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL., Hamilton-Dutoit SJ; Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark., Møller MB; Department of Pathology, Odense University Hospital, Denmark., Nørgaard P; Department of Pathology, Herlev Hospital, Herlev, Denmark., Bennani NN; Division of Hematology, Mayo Clinic, Rochester, MN., Chng WJ; Department of Hematology-Oncology, National University Cancer Institute, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Huang G; Department of Hematology-Oncology, National University Cancer Institute, Singapore., Link BK; Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA; and., Facchetti F; Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy., Cerhan JR; Department of Health Sciences Research, Mayo Clinic, Rochester, MN., d'Amore F; Department of Hematology, Aarhus University Hospital, Aarhus, Denmark., Ansell SM; Division of Hematology, Mayo Clinic, Rochester, MN., Feldman AL; Department of Laboratory Medicine and Pathology and.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2018 Sep 27; Vol. 132 (13), pp. 1386-1398. Date of Electronic Publication: 2018 Aug 09.
DOI:	10.1182/blood-2018-03-838524
Abstrakt:	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 bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22- rearranged 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. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
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