Journal article
Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements
Blood, Vol.132(13), pp.1386-1398
09/27/2018
DOI: 10.1182/blood-2018-03-838524
PMCID: PMC6161771
PMID: 30093402
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 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.
Details
- Title: Subtitle
- Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements
- Creators
- Rebecca A. Luchtel - Mayo ClinicSurendra Dasari - Mayo ClinicNaoki Oishi - University of YamanashiMartin Bjerregard Pedersen - Aarhus University HospitalGuangzhen Hu - Mayo ClinicKaren L. Rech - Mayo ClinicRhett P. Ketterling - Mayo ClinicJagmohan Sidhu - United Health ServicesXueju Wang - Jilin UniversityRyohei Katoh - University of YamanashiAhmet Dogan - Mayo ClinicN. Sertac Kip - Mayo ClinicJulie M. Cunningham - Mayo ClinicZhifu Sun - Mayo ClinicSaurabh Baheti - Mayo ClinicJulie C. Porcher - Mayo ClinicJonathan W. Said - University of California, Los AngelesLiuyan Jiang - Mayo Clinic in FloridaStephen Jacques Hamilton-Dutoit - Aarhus University HospitalMichael Boe Moller - Odense Univ Hosp, Dept Pathol, Odense, DenmarkPeter Norgaard - Herlev Hosp, Dept Pathol, Herlev, DenmarkN. Nora Bennani - Mayo ClinicWee-Joo Chng - National University of SingaporeGaofeng Huang - National University Cancer Institute, SingaporeBrian K. Link - University of Iowa Hospitals and ClinicsFabio Facchetti - University of BresciaJames R. Cerhan - Mayo ClinicFrancesco Damore - Aarhus UniversityStephen M. Ansell - Mayo ClinicAndrew L. Feldman - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.132(13), pp.1386-1398
- Publisher
- Amer Soc Hematology
- DOI
- 10.1182/blood-2018-03-838524
- PMID
- 30093402
- PMCID
- PMC6161771
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Number of pages
- 13
- Grant note
- R01CA177734 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Predolin Foundation Fraternal Order of Eagles Cancer Research Fund Mayo Clinic Cancer Center UL1 TR000135 / Clinical and Translational Science Award (CTSA) grant from the National Institutes of Health, National Center for Advancing Translational Science Department of Laboratory Medicine and Pathology, Mayo Clinic UL1TR000135 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) 123012-RSG-12-193-01-TBE / American Cancer Society CI-48-09 / Damon Runyon Cancer Research Foundation Center for Individualized Medicine, Mayo Clinic R01 CA177734; P30 CA15083; P50 CA97274 / National Institutes of Health, National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 09/27/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984359800502771
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