RESUMO
The histone methyltransferase EZH2 is frequently mutated in germinal center-derived diffuse large B-cell lymphoma and follicular lymphoma. To further characterize these EZH2 mutations in lymphomagenesis, we generated a mouse line where EZH2(Y641F) is expressed from a lymphocyte-specific promoter. Spleen cells isolated from the transgenic mice displayed a global increase in trimethylated H3K27, but the mice did not show an increased tendency to develop lymphoma. As EZH2 mutations often coincide with other mutations in lymphoma, we combined the expression of EZH2(Y641F) by crossing these transgenic mice with Eµ-Myc transgenic mice. We observed a dramatic acceleration of lymphoma development in this combination model of Myc and EZH2(Y641F). The lymphomas show histologic features of high-grade disease with a shift toward a more mature B-cell phenotype, increased cycling and gene expression, and epigenetic changes involving important pathways in B-cell regulation and function. Furthermore, they initiate disease in secondary recipients. In summary, EZH2(Y641F) can collaborate with Myc to accelerate lymphomagenesis demonstrating a cooperative role of EZH2 mutations in oncogenesis. This murine lymphoma model provides a new tool to study global changes in the epigenome caused by this frequent mutation and a promising model system for testing novel treatments.
Assuntos
Transformação Celular Neoplásica/genética , Linfoma/genética , Mutação , Complexo Repressor Polycomb 2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Western Blotting , Células da Medula Óssea/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Linfoma/metabolismo , Linfoma/patologia , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Lisina/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexo Repressor Polycomb 2/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Baço/metabolismo , Baço/patologiaRESUMO
BACKGROUND: Genetic testing is indicated for children with a personal or family history of hereditary cardiomyopathy to determine appropriate management and inform risk stratification for family members. The implications of a positive genetic result for children can potentially impact emotional well-being. Given the nuances of cardiomyopathy genetic testing for minors, this study aimed to understand how parents involve their children in the testing process and investigate the impact of genetic results on family dynamics. METHODS: A survey was distributed to participants recruited from the Children's Cardiomyopathy Foundation and 7 North American sites in the Pediatric Cardiomyopathy Registry. The survey explored adolescent and parent participants' emotions upon receiving their/their child's genetic results, parent-child result communication and its impact on family functionality, using the McMaster Family Assessment Device. RESULTS: One hundred sixty-two parents of minors and 48 adolescents who were offered genetic testing for a personal or family history of cardiomyopathy completed the survey. Parents whose child had cardiomyopathy were more likely to disclose positive diagnostic genetic results to their child (P=0.014). Parents with unaffected children and positive predictive testing results were more likely to experience negative emotions about the result (P≤0.001) but also had better family functioning scores than those with negative predictive results (P=0.019). Most adolescents preferred results communicated directly to the child, but parents were divided about whether their child's result should first be released to them or their child. CONCLUSIONS: These findings have important considerations for how providers structure genetic services for adolescents and facilitate discussion between parents and their children about results.