A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia
A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia
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DOI：
10.1016/j.cell.2014.02.019
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发表时间：
2014-04-10
期刊：
影响因子：
64.5
通讯作者：
Delwel, Ruud
中科院分区：
文献类型：
--
作者：
Groeschel, Stefan;Sanders, Mathijs A.;Delwel, Ruud
没有基因融合的染色体重排通过重新定位隐蔽的调节DNA元件引起原癌基因的失调而与白血病发生有关。AML伴inv（3）/t（3;3）与干细胞调节因子EVI 1的异常表达有关。应用功能基因组学和基因组工程，我们证明了这两个3q重排重新定位远端GATA 2增强子异位激活EVI 1，同时赋予GATA 2功能单倍不足，以前确定为散发性家族性AML/MDS和MonoMac/Emberger综合征的原因。异位增强子的基因组切除恢复了EVI 1沉默，并导致AML细胞的生长抑制和分化，这可以通过药理学BET抑制来复制。我们的数据表明，涉及单个增强子的染色体重新定位的结构重排可以导致两个不相关的远端基因的失调，从而导致癌症。
Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET inhibition. Our data show that structural rearrangements involving the chromosomal repositioning of a single enhancer can cause deregulation of two unrelated distal genes, with cancer as the outcome.