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
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.