Development and Characterization of MYB-NFIB Fusion Expression in Adenoid Cystic Carcinoma

Abstract

Adenoid cystic carcinoma (ACC) is the second most common cancer type arising from the salivary gland. The frequent occurrence of chromosome t(6,9) translocation leading to the fusion of MYB and NFIB transcription factor genes is considered a genetic hallmark of ACC. This inter-chromosomal rearrangement may encode multiple variants of functional MYB-NFIB fusion in ACC. However, the lack of an ACC model that harbors the t(6,9) translocation has limited studies on defining the potential function and implication of chimeric MYB-NFIB protein in ACC. This report aims to establish a MYB-NFIB fusion protein expressing system in ACC cells for in vitro and in vivo studies. RNA-seq data from MYB-NFIB translocation positive ACC patients’ tumors and MYB-NFIB fusion transcript in ACC patient-derived xenografts (ACCX) was analyzed to identify MYB breakpoints and their frequency of occurrence. Based on the MYB breakpoint identified, variants of MYB-NFIB fusion expression system were developed in a MYB-NFIB deficient ACC cell lines. Analysis confirmed MYB-NFIB fusion protein expression in ACC cells and ACCXs. Furthermore, recombinant MYB-NFIB fusion displayed sustained protein stability and impacted transcriptional activities of interferon-associated genes set as compared to a wild type MYB. In vivo tumor formation analysis indicated the capacity of MYB-NFIB fusion cells to grow as implanted tumors, although there were no fusion-mediated growth advantages. This expression system may be useful not only in studies to determine the functional aspects of MYB-NFIB fusion but also in evaluating effective drug response in vitro and in vivo settings.

Successful surgery with preservation of laryngeal function in a patient with collision primary squamous cell carcinoma and adenoid cystic carcinoma in the hypopharynx and synchronous esophageal carcinoma: A case report

“…The etiology and driving mechanism(s) remain unclear. Some studies have reported MYB gene aberrations in more than 70% of ACC cases 11–14 . MYB status may be prognostic of ACC 14 .…”

Genetic Rearrangements in Different Salivary Gland Tumors: A Systematic Review

“…Research in molecular biology has revealed that most ACC tumors are characterized by persistent chromosomal translocations, which initiate the activation of the MYB oncogene or its similar gene, MYBL1. In the current study, three articles were selected based on somatic mutations (Table 1) [18][19][20]. This leads to distinctive alterations in gene expression patterns [18].…”

Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical

“…Avian myeloblastosis viral oncogene homolog (MYB) is a transcriptional regulator that plays a critical role in maintaining normal tissue homeostasis and development [ 233 ]. The presence of rearrangements and mutations in the MYB gene serves as compelling evidence for the involvement of MYB family members in human cancers.…”

“…The presence of rearrangements and mutations in the MYB gene serves as compelling evidence for the involvement of MYB family members in human cancers. The most frequently occurring MYB fusion is MYB–NFIB [ 233 , 234 ] ( Figure 14 ). In particular, the AKT-dependent IGF-IR signaling pathway regulates MYB–NFIB, making the IGF-1R–MYB–NFIB axis a promising target for the treatment of ACC [ 235 ].…”