Title:	MLL2/KMT2D and MLL3/KMT2C expression correlates with disease progression and response to imatinib mesylate in chronic myeloid leukemia
Authors:	Rabello, Doralina do Amaral Ferreira, Vivian D’Afonseca da Silva Coelho, Maria Gabriela Berzoti Burin, Sandra Mara Magro, Cíntia Leticia Cacemiro, Maira da Costa Simões, Belinda Pinto Araújo, Felipe Saldanha de Castro, Fabíola Attié de Pittella-Silva, Fabio
metadata.dc.contributor.affiliation:	Universidade de Brasília, Faculdade de Medicina Universidade de Brasília, Faculdade de Ciências da Saúde, Departamento de Farmácia Departamento de Análises Clínicas, Toxicologia e Ciências Alimentares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Departamento de Análises Clínicas, Toxicologia e Ciências Alimentares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Departamento de Análises Clínicas, Toxicologia e Ciências Alimentares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Departamento de Análises Clínicas, Toxicologia e Ciências Alimentares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo Departamento de Medicina Interna, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo Universidade de Brasília, Faculdade de Ciências da Saúde, Departamento de Farmácia Departamento de Análises Clínicas, Toxicologia e Ciências Alimentares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo
Assunto::	Leucemia mielóide crônica (LMC) Inibidores Epigenética
Issue Date:	20-Feb-2018
Publisher:	BioMed Center
Citation:	RABELLO, Doralina do Amaral et al. MLL2/KMT2D and MLL3/KMT2C expression correlates with disease progression and response to imatinib mesylate in chronic myeloid leukemia. Cancer Cell International, v. 18, art. n. 26, 2018. DOI: https://doi.org/10.1186/s12935-018-0523-1. Disponível em: https://cancerci.biomedcentral.com/articles/10.1186/s12935-018-0523-1. Acesso em: 05 set. 2022.
Abstract:	Background Chronic 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. Methods 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. Results In 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. Conclusion 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.
Licença::	© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
DOI:	https://doi.org/10.1186/s12935-018-0523-1
Appears in Collections:	Artigos publicados em periódicos e afins

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