Menin-MLL inhibitor blocks progression of middle ear cholesteatoma in vivo. (January 2021)

• Record Type: Journal Article
• Authors: Yamamoto-Fukuda, Tomomi; Akiyama, Naotaro; Tatsumi, Norifumi; Okabe, Masataka; Kojima, Hiromi
• Is Part Of: International journal of pediatric otorhinolaryngology. Volume 140(2021)
• Publication Date: 2021-01
• Subjects: Cholesteatoma -- Menin-MLL inhibitor -- KGF -- p63 -- Level of evidence: N/A; Otolaryngology -- Periodicals; Pediatrics -- Periodicals; Otolaryngology -- Periodicals; Pediatrics -- Periodicals; Oto-rhino-laryngologie -- Périodiques; Pédiatrie -- Périodiques; 618.9209751
• DOI: 10.1016/j.ijporl.2020.110545
• Languages: English
• ISSNs: 0165-5876

Abstract

Abstract: Objective: Cholesteatoma is an epithelial lesion that expands into the middle ear, resulting in bone destruction. The acceleration of the proliferative activity of epithelial stem/progenitor cells is involved in the pathogenesis of cholesteatoma. Recently, the use of a menin-mixed lineage leukemia 1 (MLL1) inhibitor, MI503, in experiments has resulted in inhibition of the growth of tumors under histone modification. In this study, we investigated the effects of the menin-MLL inhibitor against cholesteatoma growth in an in vivo model. Methods: We first correlated the expression level of histone H3 trimethylation at lysine 4 (H3K4me3) among cholesteatoma cases, chronic otitis media cases and normal skin tissues. Based on the role of keratinocyte growth factor (KGF) in the development of cholesteatoma, KGF-expression vector was transfected into the ear and we analyzed the expression level of H3K4me3. After cholesteatoma was induced, MI503 was administered daily into the ear for 14 days. Results: We detected the highest labeling index of H3K4me3 in the cholesteatoma specimens. After KGF-expression vector transfection in the mouse ear, a high expression level of H3K4me3 was observed in the epithelial layers. The use of MI503 reduced cholesteatoma in the in vivo model and decreased the proliferation of epithelial stem/progenitor cells in a dose-dependent manner. Conclusion: We demonstrated that inhibition of the menin-MLL interaction may be a potentially useful strategy in the conservative treatment of cholesteatoma.