Título:	GLP overexpression is associated with poor prognosis in Chronic Lymphocytic Leukemia and its inhibition induces leukemic cell death
Autor(es):	Silva, Juliana Carvalho Rocha Alves da Carvalho, Juliana Lott de Rabello, Doralina Amaral Serejo, Teresa Raquel Tavares Rego, Eduardo Magalhães Neves, Francisco Assis Rocha Araújo, Antonio Roberto Lucena Pittella-Silva, Fabio Araújo, Felipe Saldanha de
Afiliação do autor:	Universidade de Brasília, Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular Universidade Católica de Brasília, Laboratório de Biotecnologia Universidade de Brasília, Faculdade de Ciências da Saúde, Laboratório de Patologia Molecular do Câncer Universidade de Brasília, Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular Universidade de São Paulo, Laboratório de Hematologia Universidade de Brasília, Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular Universidade Federal de Pernambuco, Laboratório de Hematologia Universidade de Brasília, Faculdade de Ciências da Saúde, Laboratório de Patologia Molecular do Câncer
Assunto:	Leucemia Enzimas Marcadores
Data de publicação:	31-Mai-2018
Editora:	Springer
Referência:	ALVES-SILVA, Juliana Carvalho et al. GLP overexpression is associated with poor prognosis in Chronic Lymphocytic Leukemia and its inhibition induces leukemic cell death. Investigational New Drugs, v. 36, p. 955-960, 2018. https://doi.org/10.1007/s10637-018-0613-x.
Abstract:	Background Heterodimeric methyltransferases GLP (EHMT1/KMT1D) and G9a (EHMT2/KMT1C) are two closely related enzymes that promote the monomethylation and dimethylation of histone H3 lysine 9. Dysregulation of their activity has been implicated in several types of human cancer. Patients and methods Here, in order to investigate whether GLP/G9a exerts any impact on Chronic Lymphocytic Leukemia (CLL), GLP/G9a expression levels were assessed in a cohort of 50 patients and the effects of their inhibition were verified for the viability of CLL cells. Also, qRT-PCR was used to investigate the transcriptional levels of GLP/G9a in CLL patients. In addition, patient samples were classified according to ZAP-70 protein expression by flow cytometry and according to karyotype integrity by cytogenetics analysis. Finally, a selective small molecule inhibitor for GLP/G9a was used to ascertain whether these methyltransferases influenced the viability of MEC-1 CLL cell lineage. Results mRNA analysis revealed that CLL samples had higher levels of GLP, but not G9a, when compared to non-leukemic controls. Interestingly, patients with unfavorable cytogenetics showed higher expression levels of GLP compared to patients with favorable karyotypes. More importantly, GLP/G9a inhibition markedly induced cell death in CLL cells. Conclusion Taken together, these results indicate that GLP is associated with a worse prognosis in CLL, and that the inhibition of GLP/G9a influences CLL cell viability. Altogether, the present data demonstrate that these methyltransferases can be potential markers for disease progression, as well as a promising epigenetic target for CLL treatment and the prevention of disease evolution.
DOI:	https://doi.org/10.1007/s10637-018-0613-x
Versão da editora:	https://link.springer.com/article/10.1007/s10637-018-0613-x
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