RESUMO
Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C2H2 zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control.
Assuntos
Araquidonato 5-Lipoxigenase/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Fatores de Transcrição Kruppel-Like/genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas/genética , Processamento Alternativo , Animais , Linhagem Celular Tumoral , Aberrações Cromossômicas , Regulação Leucêmica da Expressão Gênica , Humanos , Fator 6 Semelhante a Kruppel , Leucemia Mieloide Aguda/patologia , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1 , Fatores de Transcrição/genéticaRESUMO
The rise of direct-to-consumer advertising (DTCA) has mirrored, if not facilitated, the shift toward more active health care consumers. We used content analysis to identify models of physician-patient interaction in DTCA from the 1997 to 2006 issues of a broad sample of women's, men's, and common readership magazines. We also conducted 36 in-depth interviews to examine the ways consumers receive and regard advertising messages, and to explore their preferences for clinical communication and decision making. We identified four models of physician-patient relationships that vary in their locus of control (physician, patient, or shared) and the form of support sought or obtained in the relationship (emotional or instrumental). Whereas consumer interviews reflected references to all four models of interaction, only two appeared in DTCA. The limited range of interactions seen in these advertisements creates a lack of congruity between interaction styles found in advertisements vs. styles reported by actual consumers.
Assuntos
Publicidade/métodos , Indústria Farmacêutica/métodos , Participação do Paciente/psicologia , Pacientes/psicologia , Relações Médico-Paciente , Adolescente , Adulto , Antidepressivos/uso terapêutico , Comunicação , Tomada de Decisões , Depressão/tratamento farmacológico , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The 8;21 translocation is the most common chromosomal aberration occurring in acute myeloid leukemia (AML). This translocation causes expression of the RUNX1-ETO (AML1-ETO) fusion protein, which cooperates with additional mutations in leukemia development. We report here that interferons (IFNs) and IFN-stimulated genes are a group of genes consistently up-regulated by RUNX1-ETO in both human and murine models. RUNX1-ETO-induced up-regulation of IFN-stimulated genes occurs primarily via type I IFN signaling with a requirement for the IFNAR complex. Addition of exogenous IFN in vitro significantly reduces the increase in self-renewal potential induced by both RUNX1-ETO and its leukemogenic splicing isoform RUNX1-ETO9a. Finally, loss of type I IFN signaling via knockout of Ifnar1 significantly accelerates leukemogenesis in a t(8;21) murine model. This demonstrates the role of increased IFN signaling as an important factor inhibiting t(8;21) fusion protein function and leukemia development and supports the use of type I IFNs in the treatment of AML.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Interferon Tipo I/farmacologia , Leucemia/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Translocação Genética , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Modelos Animais de Doenças , Humanos , Leucemia/metabolismo , Camundongos , Camundongos Knockout , Proteínas de Fusão Oncogênica/metabolismo , Proteína 1 Parceira de Translocação de RUNX1 , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Células U937RESUMO
This study examined how ethnic composition and linguistic acculturation within schools affected the efficacy of a youth substance use prevention model program. Data come from a randomized trial of the keepin' it REAL program, using a predominantly Mexican American sample of middle school students in Phoenix, Arizona. Schools were randomly assigned to a control group or to one of three culturally tailored intervention versions. We hypothesized that school ethnic and linguistic acculturation composition (percent Latino, percent non-English speaking at home) and individual level of linguistic acculturation jointly would moderate the efficacy of the prevention program, as indicated by students' alcohol, marijuana, and cigarette use. Using multilevel linear modeling and multiple imputation techniques to manage clustered data and attrition, results showed that desired program effects varied by the linguistic acculturation level of the school, the program version, and individual acculturation level. The Latino intervention version was more efficacious in schools with larger percentages of non-English speaking families, but only among less linguistically acculturated Latino students. There were no significant school level program effects connected to the percentage of Latino students at school, the other versions of the program, or among more linguistically acculturated students.