Contributions
Abstract: EP381
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
With a two-year survival of <10% chromosomal rearrangements involving EVI1/MECOM represent the most adverse genetic event in acute myeloid leukemia (AML). As established treatment options commonly fail in these patients, there is an urgent need for rational therapeutic concepts that will require a better understanding of molecular and cellular functions of the EVI1 oncogene in AML.
Aims
This study aimed to identify transcriptional programs and genetic dependencies evoked by aberrant EVI1/MECOM expression in AML.
Methods
We have developed a panel of murine and human models of EVI1-driven AML that recapitulate common phenotypic and transcriptional features of human EVI1-rearranged AML, enable conditional expression of EVI1 itself, as well as the RNAi- and CRISPR/Cas9-based genetic exploration of EVI1-associated candidate targets.
Results
We have characterized transcriptional programs evoked by EVI1 in cell culture models and in vivo, and systematically identified genetic dependencies through comparative CRISPR/Cas9-based screens. By integrating orthogonal data from transcriptome profiling, we identify factors that are both, aberrantly expressed and specifically required in EVI1-driven AML. Among these, we identify aberrant activation of ERG, an ETS-related transcription factor that is overexpressed in subgroups of patients suffering from AML and T-ALL, as highly selective dependency in EVI1-driven AML. Suppression of ERG triggers potent and selective anti-leukemic effects and terminal differentiation in human and murine models of EVI1-driven AML, while ectopic expression of ERG functionally rescues loss of the EVI1 oncogene.
Conclusion
We find that a major oncogenic function of EVI1 is to drive aberrant expression of ERG and thereby maintain leukemia cells in an immature state. Interfering with this regulatory axis may provide new entry points for rational therapies that are urgently needed for this group of AML patients.
Keyword(s): Acute myeloid leukemia, EVI1, Mouse model, Transcriptional regulation
Abstract: EP381
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
With a two-year survival of <10% chromosomal rearrangements involving EVI1/MECOM represent the most adverse genetic event in acute myeloid leukemia (AML). As established treatment options commonly fail in these patients, there is an urgent need for rational therapeutic concepts that will require a better understanding of molecular and cellular functions of the EVI1 oncogene in AML.
Aims
This study aimed to identify transcriptional programs and genetic dependencies evoked by aberrant EVI1/MECOM expression in AML.
Methods
We have developed a panel of murine and human models of EVI1-driven AML that recapitulate common phenotypic and transcriptional features of human EVI1-rearranged AML, enable conditional expression of EVI1 itself, as well as the RNAi- and CRISPR/Cas9-based genetic exploration of EVI1-associated candidate targets.
Results
We have characterized transcriptional programs evoked by EVI1 in cell culture models and in vivo, and systematically identified genetic dependencies through comparative CRISPR/Cas9-based screens. By integrating orthogonal data from transcriptome profiling, we identify factors that are both, aberrantly expressed and specifically required in EVI1-driven AML. Among these, we identify aberrant activation of ERG, an ETS-related transcription factor that is overexpressed in subgroups of patients suffering from AML and T-ALL, as highly selective dependency in EVI1-driven AML. Suppression of ERG triggers potent and selective anti-leukemic effects and terminal differentiation in human and murine models of EVI1-driven AML, while ectopic expression of ERG functionally rescues loss of the EVI1 oncogene.
Conclusion
We find that a major oncogenic function of EVI1 is to drive aberrant expression of ERG and thereby maintain leukemia cells in an immature state. Interfering with this regulatory axis may provide new entry points for rational therapies that are urgently needed for this group of AML patients.
Keyword(s): Acute myeloid leukemia, EVI1, Mouse model, Transcriptional regulation