Gain-of-function mutations in the catalytic domain of DOT1L promote lung cancer malignant phenotypes via the MAPK/ERK signaling pathway
Menée à l'aide de lignées celullaires de cancer du poumon et d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel des mutations de gain de fonction au niveau du domaine catalytique de la méthyltransférase DOT1L favorisent, via l'activation de la voie de signalisation MAPK/ERK, la croissance des cellules cancéreuses et la résistance de ces dernières aux anticancéreux
Lung cancer is a lethal malignancy lacking effective therapies. Emerging evidence suggests that epigenetic enzyme mutations are closely related to the malignant phenotype of lung cancer. Here, we identified a series of gain-of-function mutations in the histone methyltransferase DOT1L. The strongest of them is R231Q, located in the catalytic DOT domain. R231Q can enhance the substrate binding ability of DOT1L. Moreover, R231Q promotes cell growth and drug resistance of lung cancer cells in vitro and in vivo. Mechanistic studies also revealed that the R231Q mutant specifically activates the MAPK/ERK signaling pathway by enriching H3K79me2 on the RAF1 promoter and epigenetically regulating the expression of downstream targets. The combination of a DOT1L inhibitor (SGC0946) and a MAPK/ERK axis inhibitor (binimetinib) can effectively reverse the R231Q-induced phenomena. Our results reveal gain-of-function mutations in an epigenetic enzyme and provide promising insights for the precise treatment of lung cancer patients. Combining a DOT1L inhibitor and a MAPK/ERK axis inhibitor reverses the malignancy of lung cancer induced by DOT1L mutations.