Journal article
Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma
Blood, Vol.133(26), pp.2776-2789
06/27/2019
DOI: 10.1182/blood.2019000626
PMID: 31101622
Abstract
Abstract Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK−, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK− ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK− ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin–bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation–sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30–IRF4–MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30–IRF4–MYC axis and cell cycle progression in a unique subset of ALCLs.
Details
- Title: Subtitle
- Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma
- Creators
- Rebecca A Luchtel - Department of Laboratory Medicine and Pathology andMichael T Zimmermann - Mayo ClinicGuangzhen Hu - Department of Laboratory Medicine and Pathology andSurendra Dasari - Mayo ClinicManli Jiang - Department of Laboratory Medicine and Pathology andNaoki Oishi - University of YamanashiHailey K Jacobs - Department of Laboratory Medicine and Pathology andYu Zeng - Tongji UniversityTanya Hundal - Department of Laboratory Medicine and Pathology andKaren L Rech - Department of Laboratory Medicine and Pathology andRhett P Ketterling - Department of Laboratory Medicine and Pathology andJeong-Heon Lee - Epigenomics AGBruce W Eckloff - Mayo ClinicHuihuang Yan - Mayo ClinicKrutika S Gaonkar - Mayo ClinicShulan Tian - Mayo ClinicZhenqing Ye - Mayo ClinicMarshall E Kadin - Roger Williams Medical CenterJagmohan Sidhu - Binghamton UniversityLiuyan Jiang - Mayo ClinicJesse Voss - Department of Laboratory Medicine and Pathology andBrian K Link - Department of Internal Medicine andSergei I Syrbu - University of Iowa Hospitals and ClinicsFabio Facchetti - University of BresciaN. Nora Bennani - Mayo ClinicSusan L Slager - Mayo ClinicTamas Ordog - Epigenomics AGJean-Pierre Kocher - Mayo ClinicJames R Cerhan - Mayo ClinicStephen M Ansell - Mayo ClinicAndrew L Feldman - Department of Laboratory Medicine and Pathology and
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.133(26), pp.2776-2789
- DOI
- 10.1182/blood.2019000626
- PMID
- 31101622
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 06/27/2019
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Pathology; Internal Medicine
- Record Identifier
- 9984186672602771
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