Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan.
Int J Pediatr Otorhinolaryngol. 2021 Jan;140:110545. doi: 10.1016/j.ijporl.2020.110545. Epub 2020 Dec 3.
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.
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.
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.
We demonstrated that inhibition of the menin-MLL interaction may be a potentially useful strategy in the conservative treatment of cholesteatoma.
胆脂瘤是一种扩展到中耳的上皮病变，导致骨质破坏。上皮干细胞/祖细胞增殖活性的加速与胆脂瘤的发病机制有关。最近，在实验中使用 Menin-Mixed Lineage Leukemia 1（MLL1）抑制剂 MI503，通过组蛋白修饰抑制肿瘤生长。在本研究中，我们研究了 Menin-MLL 抑制剂对体内模型中胆脂瘤生长的影响。
我们首先分析了胆脂瘤病例、慢性中耳炎病例和正常皮肤组织中组蛋白 H3 赖氨酸 4 三甲基化（H3K4me3）的表达水平。基于角质细胞生长因子（KGF）在胆脂瘤发育中的作用，将 KGF 表达载体转染到耳朵中，并分析 H3K4me3 的表达水平。在胆脂瘤诱导后，将 MI503 每天给药到耳朵中 14 天。
我们在胆脂瘤标本中检测到最高的 H3K4me3 标记指数。在小鼠耳朵中转染 KGF 表达载体后，上皮层中观察到 H3K4me3 的高表达水平。MI503 的使用减少了体内模型中的胆脂瘤，并以剂量依赖的方式减少了上皮干细胞/祖细胞的增殖。
我们证明抑制 Menin-MLL 相互作用可能是胆脂瘤保守治疗的一种潜在有用策略。
