Faculty Collaboration Database

Recurrent MSC ^E116K mutations in ALK-negative anaplastic large cell lymphoma. Blood 2019 Jun 27;133(26):2776-2789

Date

05/19/2019

Pubmed ID

31101622

Pubmed Central ID

PMC6598380

DOI

10.1182/blood.2019000626

Scopus ID

2-s2.0-85069235121 (requires institutional sign-in at Scopus site)   50 Citations

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, MSC ^E116K, exclusively in ALK^- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSC ^E116K 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 MSC^E116K 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. MSC^E116K 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 MSC ^E116K 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.

Author List

Luchtel RA, Zimmermann MT, Hu G, Dasari S, Jiang M, Oishi N, Jacobs HK, Zeng Y, Hundal T, Rech KL, Ketterling RP, Lee JH, Eckloff BW, Yan H, Gaonkar KS, Tian S, Ye Z, Kadin ME, Sidhu J, Jiang L, Voss J, Link BK, Syrbu SI, Facchetti F, Bennani NN, Slager SL, Ordog T, Kocher JP, Cerhan JR, Ansell SM, Feldman AL

Author

Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Basic Helix-Loop-Helix Transcription Factors
Cell Cycle
Gene Expression Regulation, Neoplastic
Humans
Lymphoma, Large-Cell, Anaplastic
Mutation