Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma

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 <i>ALK</i> rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, <i>MSC</i> ^E116K, exclusively in ALK^- ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of <i>MSC</i> ^E116K for ALK^- ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting <i>DUSP22</i> 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 <i>MYC</i> and cell cycle inhibition. Chromatin immunoprecipitation-sequencing and transcriptome analysis identified the cell cycle regulatory gene <i>E2F2</i> 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 <i>MSC</i> promoter. Finally, ALCL cells expressing <i>MSC</i> ^E116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent <i>MSC</i> mutation as a key driver of the CD30-IRF4-MYC axis and cell cycle progression in a unique subset of ALCLs.