Abstract 366: Association of MLL2/KMT2D and MLL3/KMT2C with chronic myeloid leukemia

Abstract

Abstract Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm linked to the Philadelphia chromosome presence that generates the BCR-ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) dramatically improved the treatment efficiency and survival of CML patients by targeting BCR-ABL tyrosine kinase. Although patients in the chronic phase respond well to treatment, patients in the accelerated phase or blast crisis usually show therapy resistance and CML relapse. It is crucial, therefore, to identify biomarkers to predict CML genetic evolution and resistance to TKI therapy, considering not only the effects of genetic aberrations but also the role of epigenetic alterations during the disease. Although dysregulations in epigenetic modulators such as histone methyltrasnferases have already been described for some hematologic malignancies, to date very limited data is available for CML, especially when considering the MLL2/KMT2D and MLL3/KMT2C genes of histone methyltrasnferases. Here we investigated the expression profile of both genes in CML patients in different stages of the disease, in patients showing different responses to therapy with IM and in non-neoplastic control samples. Imatinib sensitive and resistant CML cell lines were also used to investigate whether treatment with other tyrosine kinase inhibitors interfered in their expression. Both genes were either upregulated or with basal expression level during the chronic phase compared to controls. Interestingly, MLL3/KMT2C and specially MLL2/KMT2D levels decreased during disease progression correlating with distinct clinical stages. Furthermore, MLL2/KMT2D was decreased in patients resistant to IM treatment. Our results established a new association between MLL2/KMT2D and MLL3/KMT2C genes with CML and suggest that MLL2/KMT2D is associated with disease evolution and may be a potential marker to predict the development of therapy resistance. Citation Format: Doralina do Amaral Rabello Ramos, Vivian D'Afonseca da Silva Ferreira, Maria Gabriela Berzoti-Coelho, Sandra Mara Burin, Cíntia Leticia Magro, Maira da Costa Cacemiro, Belinda Pinto Simões, Felipe Saldanha-Araujo, Fabíola Attié Castro, Fábio Pittella-Silva. Association of MLL2/KMT2D and MLL3/KMT2C with chronic myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 366.