Contributions
Abstract: S427
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45
Location: Hall E
Background
Aims
Methods
Results
We showed that the GLIS2 moiety drives the megakaryocytic phenotype whereas both the ETO2 and GLIS2 moieties are required for maintaining self-renewal. Global expression profiling and comparison to patients’ signature consistently identified ETO2-GLIS2-mediated deregulation of major transcriptional regulators of hematopoiesis and leukemogenesis. Especially, ETO2-GLIS2 brings on an unbalance in ETS/GATA factors illustrated by an extinction of GATA1 and an overexpression of the ERG oncogene. We identified that ETO2-GLIS2 directly binds DNA via ETO2 complexes and through its GLIS2 moiety. Moreover, the ETO2-GLIS2 fusion localizes at half of H3K27ac-dense enhancers, so called super-enhancers, to control transcription of associated genes, in close association with ERG. Dimerization of ETO2-GLIS2 and interaction with endogenous ETO2 via its NHR2 domains were demonstrated with immunoprecipitation experiments. A NHR2 peptide-interference strategy inhibited the oligomerization, reversed the transcriptional activation at enhancers, promoted megakaryocytic differentiation and abrogated human AMKL cells maintenance in vivo. So, the interaction of ETO2-GLIS2 with ETO2 complexes is an essential node for the transcriptional control by the fusion at enhancer elements. Finally, ERG is localized at super-enhancers and is associated with up-regulation of associated genes. ERG knockdown or genetic inactivation downregulates expression of ETO2-GLIS2 targets required for leukemic cells survival. Together, the strong up-regulation of ERG by the fusion and the presence of ERG at super-enhancers suggest a feed forward mechanism to impose gene deregulation.
Conclusion
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemia, Epigenetic, transcription factor, Pediatric
Abstract: S427
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 11:30 - 11:45
Location: Hall E
Background
Aims
Methods
Results
We showed that the GLIS2 moiety drives the megakaryocytic phenotype whereas both the ETO2 and GLIS2 moieties are required for maintaining self-renewal. Global expression profiling and comparison to patients’ signature consistently identified ETO2-GLIS2-mediated deregulation of major transcriptional regulators of hematopoiesis and leukemogenesis. Especially, ETO2-GLIS2 brings on an unbalance in ETS/GATA factors illustrated by an extinction of GATA1 and an overexpression of the ERG oncogene. We identified that ETO2-GLIS2 directly binds DNA via ETO2 complexes and through its GLIS2 moiety. Moreover, the ETO2-GLIS2 fusion localizes at half of H3K27ac-dense enhancers, so called super-enhancers, to control transcription of associated genes, in close association with ERG. Dimerization of ETO2-GLIS2 and interaction with endogenous ETO2 via its NHR2 domains were demonstrated with immunoprecipitation experiments. A NHR2 peptide-interference strategy inhibited the oligomerization, reversed the transcriptional activation at enhancers, promoted megakaryocytic differentiation and abrogated human AMKL cells maintenance in vivo. So, the interaction of ETO2-GLIS2 with ETO2 complexes is an essential node for the transcriptional control by the fusion at enhancer elements. Finally, ERG is localized at super-enhancers and is associated with up-regulation of associated genes. ERG knockdown or genetic inactivation downregulates expression of ETO2-GLIS2 targets required for leukemic cells survival. Together, the strong up-regulation of ERG by the fusion and the presence of ERG at super-enhancers suggest a feed forward mechanism to impose gene deregulation.
Conclusion
Session topic: 3. Acute myeloid leukemia - Biology
Keyword(s): Leukemia, Epigenetic, transcription factor, Pediatric