Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden.
Department of Microbiology, Immunobiology and Genetics, Center for Molecular Biology of the University of Vienna, Max F. Perutz Laboratories, Vienna Biocenter (VBC), 1030 Vienna, Austria.
Sci Adv. 2022 Apr 22;8(16):eabm9987. doi: 10.1126/sciadv.abm9987. Epub 2022 Apr 20.
Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (ArgCys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL-driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal-regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.
急性髓系白血病（AML）是由白血病起始细胞引起的，这些细胞通过原发性遗传病变获得随后的分子变化，其累积效应绕过肿瘤抑制。AML 发病机制的变化不仅提供了对转化生物学的深入了解，还揭示了新的治疗机会。然而，如果可能的话，在转化的人类 AML 样本中回溯这些事件是具有挑战性的。在这里，我们使用一种具有 MLL-ENL 融合蛋白作为主要分子事件的小鼠体内模型来解决这个问题。在克隆转化后，我们鉴定并广泛验证了 ERM 蛋白 moesin 中的一个频繁发生的密码子改变（ArgCys）突变，该突变显著加速了白血病的发生。人类癌症相关的 moesin 突变在保守的精氨酸 295 残基上同样增强了 MLL-ENL 驱动的白血病发生。从机制上讲，该突变中断了 moesin 的稳定性，并赋予该蛋白一种新的活性，从而导致细胞外信号调节激酶活性增强。因此，我们的研究表明 ERM 蛋白在 AML 中具有关键作用，这也与人类癌症有关。
