RESUMO
The present study tested whether all-trans retinoic acid (ATRA) and 5-Aza-2'-deoxycitidine (5-Aza) affect AML cell differentiation and growth in vitro by acting on the CCAAT/enhancer binding protein α (C/EBPα) and c-Myc axis. After exposure to a combination of these agents, cell differentiation and growth arrest were significantly higher in human and murine MLL-AF9-expressing cells than in MLL-AF4/AF5q31-expressing cells, which were partly associated with increased expression of C/EBPα, C/EBPε, and PU.1, and decreased expression of c-Myc. These findings indicate that MLL-AF9-expressing cells are more sensitive to ATRA and 5-Aza, indicating that different MLL fusion proteins possess different epigenetic properties associated with retinoic acid pathway inactivation.
Assuntos
Azacitidina/farmacologia , Proteína alfa Estimuladora de Ligação a CCAAT/biossíntese , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Tretinoína/farmacologia , Animais , Linhagem Celular Tumoral , Metilação de DNA , Células-Tronco Hematopoéticas/efeitos dos fármacos , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Proteína de Leucina Linfoide-Mieloide/análise , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genéticaRESUMO
CCAAT/enhancer binding protein alpha (C/EBPα) induction induces monocytic differentiation even in acute myeloid leukaemia (AML). In this study, the induction/activation of C/EBPα in myelomonocytic AML was investigated using a combination of all-trans retinoic acid (ATRA) and RAD001 (Everolimus), a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Combining these agents increased PU.1, C/EBPε and C/EBPα expression, increased the p42/p30 C/EBPα ratio, and decreased C/EBPα phosphorylation at serine 21, and was accompanied by growth inhibition, induction of CD11b expression and apoptosis in AML cell lines. Thus, agents that induce sufficient levels of C/EBPα expression might be useful in treating AML.
Assuntos
Apoptose/genética , Proteínas Estimuladoras de Ligação a CCAAT/fisiologia , Diferenciação Celular/genética , Leucemia Mielomonocítica Aguda/genética , Monócitos/fisiologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Everolimo , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/fisiologia , Humanos , Imunossupressores/farmacologia , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fosforilação/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/fisiologia , Sirolimo/análogos & derivados , Sirolimo/farmacologia , Tretinoína/farmacologia , Células U937RESUMO
We developed a real time reverse transcriptase polymerase chain reaction (RT-PCR) assay system for detecting the MOZ-CBP fusion transcript and used it to monitor minimal residual disease (MRD) status in a patient with therapy related acute myeloid leukemia (t-AML) harboring t(8;16)(p11;p13). Expression of the MOZ-CBP fusion transcript was determined by RT-PCR analysis of the patient's bone marrow at the time of diagnosis. Thereafter, real time RT-PCR was used to evaluate MRD levels throughout the entire course of treatment. The sensitivity of quantitative RT-PCR for the MOZ-CBP fusion transcript was 10(-5). Below this level, MRD was classified as negative. Real time RT-PCR of the bone marrow after induction therapy showed the reduction of MOZ-CBP transcript to approximately 10(-3) level when compared to the diagnostic sample. MRD was classified as negative (< 10(-5) compared with that in the bone marrow at diagnosis) after 5 courses of chemotherapy, a level that was maintained post-allo-hematopoietic stem cell transplantation. Real time RT-PCR of the MOZ-CBP transcript is a useful tool for assessing MRD status for a patient with therapy related acute myeloid leukemia who was initially predicted to have a poor prognosis.
Assuntos
Cromossomos Humanos Par 16 , Cromossomos Humanos Par 8 , Leucemia Mieloide Aguda/genética , Segunda Neoplasia Primária/genética , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Translocação Genética , Adolescente , Feminino , Humanos , Neoplasia Residual/genética , Transcrição GênicaAssuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Doença Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Povo Asiático , Pré-Escolar , Humanos , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Fatores de TempoRESUMO
An 11-year-old girl who had been given antiepileptic drugs (AEDs) for occipital lobe epilepsy was hospitalized with alternative psychosis and dysgraphia accompanied by forced normalization of the EEG. Her epileptic seizures and psychosis disappeared after administration of carbamazepine. She developed dysgraphia for Kanji words (Japanese morphograms). The EEG showed sporadic spikes predominantly in the left occipital region, and [123I]iomazenil single-photon-emission computed tomography (IMZ-SPECT) imaging revealed an area of hypoperfusion in the left occipital lobe. Interestingly, the left posterior inferior temporal area is known to play an important role in writing Kanji words. It is assumed that abnormal discharges in the left occipital lobe were projected into the left posterior inferior temporal area and that a functional disorder in that area led to dysgraphia; however, further exploration is needed.
