BackgroundChronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm whose pathogenesis is 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. The disease shows three distinct clinical-laboratory stages: chronic phase, accelerated phase and blast crisis. 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 lysine methyltransferase MLL2/KMT2D and MLL3/KMT2C.MethodsHere 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.ResultsIn patients, both methyltransferases 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. A rescue in the expression of both MLL genes was observed in KCL22S, a CML cell line sensitive to IM, after treatment with dasatinib or nilotinib which was associated with a higher rate of apoptosis, an enhanced expression of p21 (CDKN1A) and a concomitant decrease in the expression of CDK2, CDK4 and Cyclin B1 (CCNB1) in comparison to untreated KCL22S control or IM resistant KCL22R cell line, which suggests involvement of p53 regulated pathway.ConclusionOur 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.
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.
The incidence of head and neck cancer as well as its mortality rates continues to increase, evidencing the need for diagnostic and prognostic markers that can improve clinical management of these patients. Histone Methyltransferases (HMT) are responsible for the methylation of histone tails, a mechanism important for the regulation of gene transcription, cell differentiation and proliferation. Although alterations on these enzymes have been associated with many types of cancer, their relationship with head and neck carcinogenesis is not yet understood. SUV420H1 and SUV420H2 are members of the SUV family of HMTs that contain the conserved SET domain, which catalyzes the addition of methyl groups to specific lysine residues, leading to chromatin compaction and gene repression. In the present study, we investigated the tissue expression profile of SUV420H1 and SUV420H2 using immunohistochemistry in 10 formalin-fixed paraffin-embedded human oral cancer samples and adjacent non-tumor tissues. We also investigated the alterations of SUV420H1 and SUV420H2 genes in head and neck cancer with in silico analyses from public databases. Immunohistochemistry revealed moderate to strong SUV420H1 and SUV420H2 expression in the majority of oral cancer cells, mainly with cytoplasmic staining in the invading tumor cells. In silico analyses using data from 530 head and neck squamous cell carcinoma samples (The Cancer Genome Atlas - TCGA, via cBioPortal) revealed that amplification is the most frequent genetic alteration in SUV420H1. Considering all known lysine methyltransferases, SUV420H1 was among the top three with the highest frequency of amplification. For SUV420H2, the frequency for amplification and deletion alterations was similar. The gene expression level of these methyltransferases was also analyzed. SUV420H1 showed a high expression of mRNA in head and neck cancer samples, with a moderate correlation (R: 0.588) between genetic copy number alteration and mRNA level. SUV420H2 did not show significant altered expression. In addition, SUV420H1 mRNA overexpression was associated with decreased overall survival in head and neck cancer patients (p: 0.0233). Since these enzymes are important in chromatin compaction and gene transcription repression, an increase in their expression level, as detected in this study, could lead to changes in histone methylation pattern, resulting in aberrant silencing of genes essential to maintain normal cellular function, such as tumor suppressor genes. Taken together, our data indicates a possible role of SUV420H1 in head and neck carcinogenesis, with the potential to be used as a prognostic marker for the disease. Citation Format: Doralina do Amaral Rabello Ramos, Beatriz Itai Haupt Ribeiro, Tércia Maria Mendes Lousa de Castro, Vívian D'Afonseca da Silva Ferreira, Gustavo Henrique Soares Takano, Eliza Carla Barroso Duarte, Fabiana Pirani Carneiro, Fábio Pittella Silva. Molecular analysis of histone methyltransferases SUV420H1 and SUV420H2 and their potential as prognostic markers in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2398. doi:10.1158/1538-7445.AM2017-2398
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