Adenoid cystic carcinoma (ACC) is the second most common malignancy of the salivary glands, also found at lower frequency rates in other secretory glands such as the mammary and lacrimal glands. Salivary ACCs are slow-growing but aggressive neoplasms, with propensity to perineural invasion and high recurrence rates. MYB is the most frequently altered gene in ACCs, as approximately 40% of the ACCs contain MYB-NFIB gene fusions, and the full-length MYB is overexpressed in over 50% of the fusion-negative ACCs. However, it is still unclear whether MYB activities promote ACC development. To assess the oncogenic potential of MYB in vivo, we generated transgenic mice that overexpress MYB using the TetO system. In these mice, focal MYB overexpression was directed to salivary and mammary glands using the activator line MMTV-tTA. We found that 25% of these mice developed tumors with an average latency of 23 months. Remarkably, all the tumors that developed in these mice were ACCs, and the three main phenotypic variants of human ACCs (cribriform, tubular and solid) were represented in this cohort. Using the same transgenic system, we found that the MYB-NFIB fusion also induced ACCs, with similar incidence and lower latency. Immunohistochemical analysis of these mouse ACCs for several biomarkers of human ACC, including p63 and c-kit, provided additional evidence of the similarity of the mouse ACCs that developed in these models, and human ACCs. RNAseq global expression profiling uncovered the activation of several cancer-associated pathways in MYB-induced mouse ACCs. Most notably, activation NOTCH signaling was highly enriched in these tumors. Additional analysis for the presence of the NOTCH intracellular domain demonstrated that all of the MYB- and MYB-NFIB-induced ACCs contain NOTCH activation. These findings, and the recent identification of activating mutations in NOTCH1 and NOTCH2 in human ACCs, suggest that NOTCH activities may contribute to ACC development. To test this hypothesis, ongoing studies in the lab are directed to assess the role of NOTCH signaling in ACC development, by generating mouse models in which constitutive activation of NOTCH is induced in mice alone or in combination with MYB alterations. Overall, these studies demonstrate that MYB activities are the main oncogenic driver of ACC. Genomic rearrangements that result in MYB-NFIB fusions may enhance the oncogenic potential of MYB.

Citation Format: Yuan Hu, Xiaoyuan Zhu, Han Luo, Adel El-Naggar, Carlos Caulin. MYB and the MYB-NFIB fusion induce adenoid cystic carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1611.