Program DHC-Virtual
20 - 21 January 2021
Abstracts Myeloid session 3
Abstract
Enhancer targeting in 3q26 rearranged AML
21 January
09:06 09:18
L. Smeenk
Paper

An essential role for MYB in driving EVI1 overexpression in 3q26 rearranged acute myeloid leukemia 

Leonie Smeenk (1,2), Sophie Ottema (1,2), Roger Mulet Lazaro (1,2), Marije Havermans (1,2), Andrea Arricibita Varea (1,2), Dorien Pastoors (1,2), Stanley van Herk (1,2), Claudia Erpelinck (1,2), Tim Grob (1), Eric Bindels (1), Alex Kentsis (3), Johannes Zuber (4), Ruud Delwel (1,2)
(1) Erasmus MC, Department of Hematology, Rotterdam, (2) Oncode Institute, Erasmus MC, Rotterdam, (3) Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, USA , (4) Research Institute of Molecular Pathology, Vienna, Austria
No potential conflicts of interest
Introduction

Chromosomal inversion or translocation between 3q21 and 3q26 results in the aberrant expression of the proto-oncogenic transcription factor EVI1 located at 3q26 causing the development of Acute Myeloid Leukemia (AML). Using functional genomics and genome editing, it has been shown that in those AMLs, a single GATA2 enhancer at chromosome 3q21 translocates to 3q26 and turns into a hyperactive super-enhancer driving aberrant expression of EVI1. In this study we aimed to unravel the mechanism of EVI1 oncogene activation by the hijacked enhancer involved in 3q26 translocation. 

Methods

We applied an unbiased CRISPR/Cas9 scanning approach of the 18kb minimal translocated region of the GATA2  enhancer to uncover important transcription factor binding elements to thereby better understand the mechanisms of altered expression of the EVI1 gene.

Results

The unbiased CRISPR/Cas9 scan of the translocated GATA2 enhancer region in 3q26 rearranged AMLs unraveled the importance of only one region of approximately 1 kb of open chromatin to be essential for EVI1 activation and consequently leukemia development. This enhancer element contained several conserved transcription factor DNA binding motifs, among which a MYB DNA binding element was demonstrated to be highly essential. MYB binds to the translocated GATA2 enhancer and a strong decrease of EVI1 expression was observed upon mutating the MYB-binding site or disruption of MYB binding to the translocated GATA2 enhancer. Exposure of AML cells with an inv(3;3) or t(3;3) to a peptide which targets MYB activity by abrogating the MYB/P300 complex, resulted in reduction of EVI1 expression causing myeloid differentiation of the cells. 

Conclusion

Our data showed an essential role for MYB in the regulation of EVI1 expression, thereby suggesting that interfering with EVI1 expression via MYB in 3q26 AMLs may provide a new entry point for targeting these AMLs.

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