Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia
Oncogenic homeodomain transcription factor E2A-Pbx1 activates a novel WNT gene in pre-B acute lymphoblastoid leukemia
复制标题
DOI：
10.1073/pnas.96.20.11464
复制
发表时间：
1999-09-28
影响因子：
11.1
通讯作者：
Murre, C
中科院分区：
文献类型：
--
作者：
McWhirter, JR;Neuteboom, STC;Murre, C
大部分儿童前 B 型急性淋巴细胞白血病 (ALL) 始终含有 t(1;19) 染色体易位。 t(1;19) 易位导致产生嵌合转录因子，其中 E2A 的 N 端反式激活结构域与 Pbx1 的 C 端 DNA 结合同源结构域融合，在这里，我们表明 E2A-Pbx1 融合蛋白激活新型 WNT 基因 WNT-16 的表达，WNT-16 通常在外周淋巴器官（如脾脏、阑尾和淋巴结）中表达，但不在骨中表达相比之下，来自携带 E2A-Pbx1 杂合基因的 pre-B ALL 患者的骨髓和细胞系中存在高水平的 WNT-16 转录物。 E2A-Pbxl表达的抑制导致WNT-16 mRNA水平显着降低，表明WNT-16是E2A-Pbxl的下游靶标。三种假定的WNT受体FZ-2、FZ-3和FZ-5在B谱系的细胞中表达，包括异常表达WNT-16的前B ALL细胞。我们提出 WNT-16 介导的自分泌生长机制有助于 t(1;19) pre-B ALL 的发展。
A large fraction of pediatric pre-B acute lymphoblastoid leukemias (ALL) consistently contain a t(1;19) chromosomal translocation. The t(1;19) translocation results in the production of a chimeric transcription factor containing the N-terminal transactivation domain of E2A fused to the C-terminal DNA-binding homeodomain of Pbx1, Here, we show that the E2A-Pbx1 fusion protein activates the expression of a novel WNT gene, WNT-16, WNT-16 normally is expressed in peripheral lymphoid organs such as spleen, appendix, and lymph nodes, but not in bone marrow, In contrast, high levels of WNT-16 transcripts are present in bone marrow and cell lines derived from pre-B ALL patients carrying the E2A-Pbx1 hybrid gene. Inhibition of E2A-Pbxl expression leads to a significant decrease in WNT-16 mRNA levels, suggesting that WNT-16 is a downstream target of E2A-Pbxl, Three putative WNT receptors, FZ-2, FZ-3, and FZ-5, are expressed in cells of the B lineage, including pre-B ALL cells aberrantly expressing WNT-16. We propose that a WNT-16-mediated autocrine growth mechanism contributes to the development of t(1;19) pre-B ALL.