Identification and Characterization of a Musculin Mutant in Lymphoma

The genomic landscape of anaplastic large-cell lymphomas (ALCL), a common group of T-cell non-Hodgkin lymphomas (T-NHL), has been largely unexplored. As a result, unique targets for therapies to treat this diverse set of aggressive malignancies are lacking. To identify potential drivers of ALCL, Luchtel, Zimmermann, and colleagues performed exome sequencing of 62 T-NHLs and identified a recurrent E116K mutation within the ERXR motif of the DNA-binding domain of musculin (MSC), a transcription factor that heterodimerizes with other transcription factors to regulate lymphocyte development. Additional sequencing revealed that the MSC^E116K variant occurs almost exclusively in ALK-negative ALCLs harboring DUSP22 rearrangements and was not identified in ALK-positive or TP63-rearranged ALCL. MSC^E116K significantly increased protein expression of musculin in both patient samples and cell lines. Transduction of the MSC^E116K variant into CD4⁺ T cells and ALCL cells resulted in significant increases in cell growth compared with MSC^WT. Disruption of the DNA-binding motif subsequently disrupted the ability of MSC^E116K to bind to canonical target sequences and sequestered known heterodimerization partners such as E2A and HEB. Further, MSC^E116K also reduced expression of E2F2, a transcription factor involved in the repression of cell-cycle progression; overexpression of E2F2 resulted in decreased expression of CD30 and MYC. Compared with MSC^WT, MSC^E116K upregulated the CD30-IRF4-MYC axis, increasing expression of TNFRSF8, CD30, MYC, and IRF4. As IRF4 was shown to regulate expression of musculin, this positive feedback loop is an important driver of cell-cycle progression in ALCL. Consistent with these findings, analysis of ALCL MSC^E116K patient specimens revealed increased MYC expression. Treatment of ALCL cells overexpressing MSC^E116K with a bromodomain and extraterminal domain (BET) inhibitor significantly decreased cell growth and reduced cell viability compared with cells overexpressing MSC^WT. Collectively, these data identify a recurrent MSC mutation that drives cell-cycle progression in T-NHL and suggest a potential therapeutic strategy for patients with ALK-negative ALCL.

Lutchel RA, Zimmermann MT, Hu G, Dasari S, Jiang M, Oishi N, et al. Recurrent MSC^E116K mutations in ALK-negative anaplastic large cell lymphoma. Blood 2019 May 17 [Epub ahead of print].

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