Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia
| Autor: | Ruud Delwel, Eric M.J. Bindels, Sophie Ottema, Marije Havermans, Emery H. Bresnick, François G. Kavelaars, Andrea Arricibita Varea, Johannes Zuber, Alex Kentsis, Remco Hoogenboezem, Anja Ebert, Roger Mulet-Lazaro, Tim Grob, Daniel R. Matson, Dorien Pastoors, Michaela Fellner, Stanley van Herk, Claudia A.J. Erpelinck-Verschueren, Leonie Smeenk |
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| Přispěvatelé: | Hematology, Internal Medicine |
| Rok vydání: | 2020 |
| Předmět: |
Genes
myb GATA2 Myeloid leukemia Oncogenes Biology medicine.disease MDS1 and EVI1 Complex Locus Protein Translocation Genetic Article Cell biology GATA2 Transcription Factor Leukemia Leukemia Myeloid Acute Enhancer Elements Genetic Oncology Transcription (biology) medicine Humans MYB Sequence motif Enhancer Transcription factor |
| Zdroj: | Cancer Discov Cancer Discovery, 11(11), 2868-2883. American Association for Cancer Research Inc. |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for EVI1 transcription. Using this approach, we pinpointed a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression. This element contained a DNA-binding motif for the transcription factor MYB, which specifically occupied this site at the translocated allele and was dispensable for GATA2 expression. MYB knockout as well as peptidomimetic blockade of CBP/p300-dependent MYB functions resulted in downregulation of EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1 transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs. Significance: We show a novel paradigm in which chromosomal aberrations reveal critical regulatory elements that are nonfunctional at their endogenous locus. This knowledge provides a rationale to develop new compounds to selectively interfere with oncogenic enhancer activity. This article is highlighted in the In This Issue feature, p. 2659 |
| Databáze: | OpenAIRE |
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