MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3)
MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3)
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DOI：
10.1073/pnas.94.16.8732
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发表时间：
1997-08-05
影响因子：
11.1
通讯作者：
ZeleznikLe, NJ
中科院分区：
文献类型：
--
作者：
Sobulo, OM;Borrow, J;ZeleznikLe, NJ
重复易位t(11;16)(q23;p13.3)仅在用靶向DNA拓扑异构酶II的药物治疗继发的急性白血病或骨髓增生异常的病例中被记录。我们发现MLL基因与编码CEP（CREB结合蛋白）的基因融合，CEP在这种易位中与DNA结合蛋白CREB（cAMP反应元件结合蛋白）特异性结合。在两名患者中，MLL 与 CBP 的不同外显子框内融合，产生嵌合蛋白，其中含有 AT 钩子、甲基转移酶同源结构域和与 CREB 结合结构域或 CBP 溴结构域融合的 MLL 转录抑制结构域。两种融合产物都保留了 CBP 的组蛋白乙酰转移酶结构域，并可能通过促进 MLL AT-hooks 靶向的基因组区域的组蛋白乙酰化而导致白血病，从而通过异常染色质组织导致转录失调。CBP 是 MLL 的第一个伙伴基因，包含明确的结构和功能基序，为这些易位促进白血病发生的潜在机制提供了独特的见解。
The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase Il. We show that the MLL gene is fused to the gene that codes for CEP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization, CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.