Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia.
Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia.
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DOI：
10.1158/2159-8290.cd-20-1793
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发表时间：
2021-11
期刊：
影响因子：
28.2
通讯作者：
Delwel R
中科院分区：
文献类型：
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作者：
Smeenk L;Ottema S;Mulet-Lazaro R;Ebert A;Havermans M;Varea AA;Fellner M;Pastoors D;van Herk S;Erpelinck-Verschueren C;Grob T;Hoogenboezem RM;Kavelaars FG;Matson DR;Bresnick EH;Bindels EM;Kentsis A;Zuber J;Delwel R
在伴有inv（3）（q21;q26）或t（3;3）（q21;q26）的急性髓性白血病（AML）中，易位的GATA 2增强子驱动EVI 1的致癌表达。我们生成了EVI 1-GFP AML模型，并应用无偏CRISPR/Cas9增强子扫描来揭示EVI 1转录所必需的序列基序。使用这种方法，我们确定了一个单一的调控元件在易位的GATA 2增强子，这是非常需要的异常EVI 1的表达。该元件含有转录因子MYB的DNA结合基序，该基序特异性地占据易位等位基因的该位点，并被GATA 2表达抑制。MYB基因敲除以及CBP/p300依赖性MYB功能的拟肽阻断导致EVI 1下调，但不导致GATA 2下调。靶向MYB或突变其在GATA 2增强子内的DNA结合基序导致骨髓分化和细胞死亡，表明干扰MYB驱动的EVI 1转录为inv（3）/t（3;3）AML的治疗提供了潜在的切入点。
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.