Purchase this article with an account.
Wensi Tao, Catherine Choi, Ravi Doddapaneni, David T Tse, Daniel Pelaez; The role of MYB and NOTCH in the oncogenesis of adenoid cystic carcinoma of the lacrimal gland. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4960. doi: https://doi.org/.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Lacrimal Gland Adenoid Cystic Carcinoma (LGACC) is a rare but devastating cancer with a propensity for perineural invasion and poor prognosis. MYB oncogene overexpression and the MYB-NFIB translocation t(6;9) resulting in a fusion transcript have been previously demonstrated in breast and salivary gland ACC. Previously, whole exome sequencing of lacrimal gland ACC was performed to identify the genomic mutation profile of these tumors. The Notch signaling pathway has also been shown to be involved in tumor growth, invasion, and migration downstream of MYB. In this study, we explored the molecular mechanisms behind the MYB- and Notch-mediated pathways in tissue cultures of lacrimal gland ACC and benign mixed tumor (BMT).
LGACC and BMT tissues were obtained from surgical specimens under an institutional review board (IRB)-approved protocol. Tissue cultures were maintained under optimized cultures conditions. Both ACC and BMT cell lines were characterized using immunofluorescence and western blot. Chromosome translocation t(6;9) and MYB-NFIB fusion were detected by fluorescence in situ hybridization (FISH). Lastly, using transgenic mice with constitutively active notch intracellular domain (NICD), lentiviral vectors expressing MYB were used to induce the possible oncogenic initiators of ACC in mice.
In LGACC and BMT tissue cultures, expression of MYB and NICD were demonstrated via immunofluorescence and western blot. There was relative overexpression of both MYB and NICD in ACC compared to normal lacrimal gland and BMT. Whole exome sequencing of ACC revealed functionally significant mutations in NOTCH1, NOTCH2, and NOTCH3, as well as components of the Notch signaling pathway. Our FISH data further demonstrated there is MYB-NFIB translocation in one copy of the genome. The effect of MYB overexpression on NICD transgenic mice is expected to further corroborate the MYB- and NICD- mediated cell growth and oncogenic pathways leading to ACC.
The pathogenic mechanism behind lacrimal gland ACC still remains largely elusive. Recent developments have led to the identification of overexpression and dysregulation of both MYB and NOTCH as key markers and players in the oncogenic pathway. This study serves to further characterize the relevant pathways in both ACC and BMT to lead the way for future development of potential therapeutic targets.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only