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Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma

Rebecca A. Luchtel, Michael T. Zimmermann, Guangzhen Hu, Surendra Dasari, Manli Jiang, Naoki Oishi, Hailey K. Jacobs, Yu Zeng, Tanya Hundal, Karen L. Rech, Rhett P. Ketterling, Jeong-Heon Lee, Bruce W. Eckloff, Huihuang Yan, Krutika S. Gaonkar, Shulan Tian, Zhenqing Ye, Marshall E. Kadin, Jagmohan Sidhu, Liuyan Jiang, Jesse Voss, Brian K. Link, Sergei I. Syrbu, Fabio Facchetti, N. Nora Bennani, Susan L. Slager, Tamas Ordog, Jean-Pierre Kocher, James R. Cerhan, Steve Ansell and Andrew L. Feldman

Key Points

  • A novel MSCE116K mutation occurs exclusively in ALK-negative ALCLs, particularly those with DUSP22 rearrangements.

  • MSCE116K induces expression of the CD30-IRF4-MYC axis, drives cell cycle progression, and can be targeted with BET inhibitors.

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 ALK-positive or ALK-negative, 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-negative ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK-negative ALCL and further demonstrated that 14/15 mutated cases (93%) had co-existing 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, while 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.

  • Submitted September 19, 2018.
  • Revision received April 24, 2019.
  • Accepted April 24, 2019.