The PEBP2βMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia
The PEBP2βMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia
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DOI：
10.1073/pnas.95.20.11863
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发表时间：
1998-09-29
影响因子：
11.1
通讯作者：
Bishop, JM
中科院分区：
文献类型：
--
作者：
Kogan, SC;Lagasse, E;Bishop, JM
涉及编码Pebp 2/Cbf转录因子α和β亚基的基因的染色体易位与人急性髓性白血病和白血病前期病症骨髓增生异常有关，Inv（16）（p13;q22）将编码Pebp 2 β亚基的基因融合到编码平滑肌肌球蛋白重链（Smmhc）的MYH 11基因。q22）对骨髓生成的影响，我们使用hMRP 8启动子元件来产生在骨髓细胞中表达Pebp 2 β Smmhc嵌合融合蛋白的转基因小鼠。在PEBP 2 β MYH 11转基因小鼠中，神经元成熟受损。尽管转基因小鼠的循环中性粒细胞数量正常，但它们的骨髓中含有数量增加的未成熟嗜中性粒细胞，这些细胞表现出异常特征。此外，PEBP 2 β MYH 11抑制源自造血祖细胞的集落中的嗜酸性分化。PEBP 2 β MYH 11和活化的NRAS两者的共表达诱导了更严重的表型，其特征在于指示粒细胞发育不良的异常核形态。这些结果表明，PEBP 2 β MYH 11可以损害中性粒细胞发育，并提供了Pebp 2的改变可以促进骨髓发育不良发生的证据。
Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia, Inv(16)(p13;q22) fuses the gene encoding the beta subunit of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy chain (Smmhc), To examine the effect of the inv(16)(p13;q22) on myelopoiesis, we used the hMRP8 promoter element to generate transgenic mice expressing the Pebp2 beta Smmhc chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired in PEBP2 beta MYH11 transgenic mice. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, PEBP2 beta MYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2 beta MYH11 and activated NRAS induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia, These results show that PEBP2 beta MYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia.