Background NUT midline carcinoma (NMC) is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck (HN). HNNMC characteristics and optimal management are unclear. Methods We performed a retrospective review of all known cases of HNNMC in the International NMC Registry, data as of December 31, 2014. Of 48 consecutive patients treated from 1993–2014, clinicopathologic variables and outcomes from 40 patients were available for analyses, the largest cohort of HN NMC studied to date. Overall survival (OS) and progression-free survival (PFS) according to patient characteristics and treatment were analyzed. Results We identified a five-fold increase in diagnosis of HNNMC from 2011 to 2014. Median age was 21.9 years (range 0.1–81.7), male:female was 40%:60%, and 86% had BRD4-NUT fusion. Initial treatment was initial surgery (S) +/− adjuvant chemoradiation (CRT) or adjuvant radiation (RT) (56%), initial RT +/− chemotherapy (C) (15%), or initial C +/− S or RT (28%). Median PFS was 6.6 months (range 4.7–8.4). Median OS was 9.7 months (range 6.6–15.6). Two-year PFS was 26% (95% CI, 13%–40%). Two-year OS was 30% (95% CI, 16%–46%). Initial S +/− post-operative CRT or RT (p=0.04), and complete resection with negative margins (p=0.01) were significant predictors of improved OS even after adjustment for age, tumor size and neck lymphadenopathy. Initial RT or C, and NUT translocation type were not associated with outcome. Conclusions HNNMC portends a poor prognosis. Aggressive initial surgical resection +/− post-operative CRT or RT was associated with significantly enhanced survival. C or RT alone is often inadequate.

NUT midline carcinoma (NMC) is an aggressive type of squamous cell carcinoma that is defined by the presence of BRD-NUT fusion oncogenes, which encode chimeric proteins that block differentiation and maintain tumor growth. BRD-NUT oncoproteins contain two bromodomains whose binding to acetylated histones is required for the blockade of differentiation in NMC, but the mechanisms by which BRD-NUT act remain uncertain. Here we provide evidence that MYC is a key downstream target of BRD4-NUT. Expression profiling of NMCs show that the set of genes whose expression is maintained by BRD4-NUT is highly enriched for MYC upregulated genes, and MYC and BRD4-NUT protein expression is strongly correlated in primary NMCs. More directly, we find that BRD4-NUT associates with the MYC promoter and is required to maintain MYC expression in NMC cell lines. Moreover, both siRNA knockdown of MYC and a dominant-negative form of MYC, omomyc, induce differentiation of NMC cells. Conversely, differentiation of NMC cells induced by knockdown of BRD4-NUT is abrogated by enforced expression of MYC. Together, these findings suggest that MYC is a downstream target of BRD4-NUT that is required for maintenance of NMC cells in an undifferentiated, proliferative state. Our findings support a model in which dysregulation of MYC by BRD-NUT fusion proteins has a central role in the pathogenesis of NMC.