RESUMO
High expression of the transcriptional regulator EVI1 encoded at the MECOM locus at 3q26 is one of the most aggressive oncogenic drivers in acute myeloid leukemia (AML) and carries a very poor prognosis. How EVI1 confers leukemic transformation and chemotherapy resistance in AML is subject to important ongoing clinical and experimental studies. Recent discoveries have revealed critical details on genetic mechanisms of the activation of EVI1 overexpression and downstream events of aberrantly high EVI1 expression. Here we review and discuss aspects concerning the protein interactions of EVI1 and the related proteins MDS-EVI1 and ΔEVI1 from the perspective of their potential for therapeutic intervention.
Assuntos
Proteínas de Ligação a DNA , Leucemia Mieloide Aguda , Proteínas de Ligação a DNA/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/genética , Prognóstico , Fatores de Transcrição/metabolismoRESUMO
Early detection and prevention of psychosis has become an international priority. Much of this work has focused on youth presenting with attenuated symptoms of psychosis-those at Clinical High Risk for psychosis (CHR)-given their elevated probability of developing the full disorder in subsequent years. Individuals at CHR may be prone to exacerbated psychological distress during the COVID-19 pandemic and its subsequent physical isolation measures, due to heightened stress sensitivity and comorbid mental health problems. Telepsychotherapy holds promise for reaching this population, especially during the current COVID-19 outbreak. However, there are limited evidence-based guidelines or interventions for use of telepsychotherapy with this population. In this paper, we review common clinical issues for individuals at CHR and how they might be exacerbated by the COVID-19 pandemic; best practices for treatment and adaptations for telepsychotherapy for individuals at CHR; and highlight real clinical issues that we are currently experiencing in a United States-based specialized CHR clinic as we conduct telepsychotherapy via videoconferencing. We conclude with questions for those in the field to contemplate, as well as potential challenges and benefits in using telepsychotherapy with individuals at CHR and their families.
RESUMO
The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. In the presence of genotoxic stress EVI1-WT (SQS), but not site mutated EVI1-AQA was able to maintain transcriptional patterns and transformation potency, while under standard conditions carboxy-terminal mutation had no effect. Maintenance of hematopoietic progenitor cell clonogenic potential was profoundly impaired with EVI1-AQA compared with EVI1-WT, in particular in the presence of genotoxic stress. Exploring mechanistic events underlying these observations, we showed that after genotoxic stress EVI1-WT, but not EVI1-AQA increased its level of association with its functionally essential interaction partner CtBP1, implying a role for ATM in regulating EVI1 protein interactions via phosphorylation. This aspect of EVI1 regulation is therapeutically relevant, as chemotherapy-induced genotoxicity might detrimentally sustain EVI1 function via stress response mediated phosphorylation, and ATM-inhibition might be of specific targeted benefit in EVI1-overexpressing malignancies.
Assuntos
Oxirredutases do Álcool/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Autorrenovação Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Leucêmica da Expressão Gênica , Proteína do Locus do Complexo MDS1 e EVI1/genética , Doença Aguda , Oxirredutases do Álcool/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Proteína do Locus do Complexo MDS1 e EVI1/química , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Mutação , FosforilaçãoRESUMO
The Patient Protection and Affordable Care Act focuses on improving consumer engagement and patient-centered care. This article describes the design and rationale of a study targeting family engagement in pediatric mental health services. The study is a 90-day randomized trial of a telephone-delivered Family Navigator services versus usual care for parents of Medicaid-insured youth younger than 13 years with serious mental illness. Youth are identified through a pediatric antipsychotic medication preauthorization program. Family Navigators offer peer support to empower and engage parents in their child's recovery. Outcomes include parent report of empowerment, social support, satisfaction with child mental health services, and child functioning as well as claims-based measures of psychotherapy service utilization and antipsychotic medication dosage. The focus on "family-centered" care in this study is strongly supported by the active role of consumers in study design and implementation.
