N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

Frerich, Candace A.; Sedam, Hailey N.; Kang, Huining; Mitani, Yoshitsugu; El‐Naggar, Adel K.; Ness, Scott A.

doi:10.3390/cancers12010045

Cited by 21 publications

(13 citation statements)

References 54 publications

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“…Expression of truncated variants of MYB, corresponding to alternative promoter usage, has previously been shown to result in altered MYB‐regulated downstream gene expression 19 . In our study, high MYB TSS2 activity was associated with decreased expression of conventional MYB target genes and increased expression of genes involved in KRAS signaling and transmembrane transport.…”

Section: Discussionsupporting

confidence: 55%

“…The transcriptional regulation of MYB is complex with an alternative MYB promoter located in intron 1 that is differentially activated between normal and leukemic cells 17,18 . Expression of the alternative MYB promoter was recently demonstrated also in primary adenoid cystic carcinomas 19 . Notably, ectopic expression of N‐terminally truncated forms of MYB, corresponding to alternative promoter usage, resulted in an altered MYB downstream target gene repertoire.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 Expression of the alternative MYB promoter was recently demonstrated also in primary adenoid cystic carcinomas. 19 Notably, ectopic expression of N-terminally truncated forms of MYB, corresponding to alternative promoter usage, resulted in an altered MYB downstream target gene repertoire. In this study, we have investigated the clinical significance of MYB alternative promoter activity in a large, well-characterized cohort of 133 pediatric ALLs with clinical follow-up data.…”

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confidence: 99%

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Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia

Fehr

Arvidsson

Nordlund

et al. 2023

Genes Chromosomes & Cancer

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Therapy-resistant disease is a major cause of death in patients with acute lymphoblastic leukemia (ALL). Activation of the MYB oncogene is associated with ALL and leads to uncontrolled neoplastic cell proliferation and blocked differentiation. Here, we used RNA-seq to study the clinical significance of MYB expression and MYB alternative promoter (TSS2) usage in 133 pediatric ALLs. RNA-seq revealed that all cases analyzed overexpressed MYB and demonstrated MYB TSS2 activity. qPCR analyses confirmed the expression of the alternative MYB promoter also in seven ALL cell lines. Notably, high MYB TSS2 activity was significantly associated with relapse (p = 0.007). Moreover, cases with high MYB TSS2 usage showed evidence of therapy-resistant disease with increased expression of ABC multidrug resistance transporter genes (e.g., ABCA2, ABCB5, and ABCC10) and enzymes catalyzing drug degradation (e.g., CYP1A2, CYP2C9, and CYP3A5). Elevated MYB TSS2 activity was further associated with augmented KRAS signaling (p < 0.05) and decreased methylation of the conventional MYB promoter (p < 0.01). Taken together, our results suggest that MYB alternative promoter usage is a novel potential prognostic biomarker for relapse and therapy resistance in pediatric ALL.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia

Fehr

Arvidsson

Nordlund

et al. 2023

Genes Chromosomes & Cancer

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“…Interestingly, as noted anecdotally by the authors previously, none of the cases were seen in major salivary glands, and most were seen in seromucous glands with only occasional cases in oral cavity. The other interesting question is whether there is any significance to MYB being in the 5′ position in these novel fusions, instead of the more typical 3′ position of canonical fusions 19. Since MYB gene overexpression is considered enough to drive adenoid cystic carcinogenesis without a novel chimeric protein,20 it is speculated that the method of this overexpression has no material impact on the development of these cases.…”

Section: Discussionmentioning

confidence: 99%

Adenoid Cystic Carcinoma With Striking Tubular Hypereosinophilia

Weinreb

Rooper

Dickson

et al. 2023

American Journal of Surgical Pathology

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The classification of salivary gland tumors is ever-evolving with new variants of tumors being described every year. Next-generation sequencing panels have helped to prove and disprove prior assumptions about tumors’ relationships to one another, and have helped refine this classification. Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs at all major and minor salivary gland and seromucous gland sites. Most AdCC are predominantly myoepithelial and basaloid with variable cribriform, tubular, and solid growth. The luminal tubular elements are often less conspicuous. AdCC has largely been characterized by canonical MYB fusions, with MYB::NFIB and rarer MYBL1::NFIB. Anecdotal cases of AdCC, mostly in nonmajor salivary gland sites, have been noted to have unusual patterns, including squamous differentiation and macrocystic growth. Recently, this has led to the recognition of a subtype termed “metatypical adenoid cystic carcinoma.” Another unusual histology that we have seen with a wide range of architecture, is striking tubular hypereosinophilia. The hypereosinophilia and luminal cell prominence is in stark contrast to the vast majority of AdCC that are basaloid and myoepithelial predominant. A total of 16 cases with tubular hypereosinophilia were collected, forming morular, solid, micropapillary, and glomeruloid growth, and occasionally having rhabdoid or Paneth-like cells. They were subjected to molecular profiling demonstrating canonical MYB::NFIB (5 cases) and MYBL1::NFIB (2 cases), as well as noncanonical EWSR1::MYB (2 cases) and FUS::MYB (1 case). The remaining 6 cases had either no fusion (3 cases) or failed sequencing (3 cases). All cases were present in nonmajor salivary gland sites, with seromucous glands being the most common. These include sinonasal tract (7 cases), laryngotracheal (2 cases), external auditory canal (2 cases), nasopharynx (1 case), base of tongue (2 cases), palate (1 case), and floor of mouth (1 case). A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions.

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“…MYB itself can contribute to intratumoral heterogeneity by driving distinct expression programs in myoepithelial cells versus luminal cell lineages 146 . An alternative MYB promoter was also recently discovered that produces an N‐terminally truncated MYB protein that drives a distinct transcriptional signature from full‐length protein 158 . Single‐cell RNA sequencing has confirmed significant heterogeneity in both the malignant and stromal compartments of ADCC tumors, including the discovery that the ADCC‐I and ADCC‐II signatures delineated in bulk sequencing can be observed within individual cell populations in all ADCCs and that NOTCH activation in luminal cells is likely activated through paracrine interactions with myoepithelial cells 159 .…”

Section: Immunotherapy For Salivary Gland Cancersmentioning

confidence: 99%

The evolving landscape of salivary gland tumors

Steuer

Hanna

Viswanathan

et al. 2023

CA A Cancer J Clinicians

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Salivary gland cancers are a rare, histologically diverse group of tumors. They range from indolent to aggressive and can cause significant morbidity and mortality. Surgical resection remains the mainstay of treatment, but radiation and systemic therapy are also critical parts of the care paradigm. Given the rarity and heterogeneity of these cancers, they are best managed in a multidisciplinary program. In this review, the authors highlight standards of care as well as exciting new research for salivary gland cancers that will strive for better patient outcomes.

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N-Terminal Truncated Myb with New Transcriptional Activity Produced Through Use of an Alternative MYB Promoter in Salivary Gland Adenoid Cystic Carcinoma

Cited by 21 publications

References 54 publications

Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia

Increased MYB alternative promoter usage is associated with relapse in acute lymphoblastic leukemia

Adenoid Cystic Carcinoma With Striking Tubular Hypereosinophilia

The evolving landscape of salivary gland tumors

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