Shimizu K, Kitabayashi I, Kamada N, Abe T, Maseki N, Suzukawa K, Ohki M
Radiobiology Division, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Blood. 2000 Jul 1;96(1):288-96.
The t(8;21) translocation is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). In this translocation, the AML1 (CBFA2/PEBP2aB) gene is disrupted and fused to the MTG8 (ETO) gene. The ectopic expression of the resulting AML1-MTG8 fusion gene product in L-G and 32Dcl3 murine myeloid precursor cells stimulates cell proliferation without inducing morphologic terminal differentiation into mature granulocytes in response to granulocyte-colony stimulating factor (G-CSF). This study found that the ectopic expression of AML1-MTG8 elevates the expression of the G-CSF receptor (G-CSFR). Analysis of the promoter region of the G-CSFR gene revealed that up-regulation of G-CSFR expression by AML1-MTG8 does not depend on the AML1-binding sequence, but on the C/EBP (CCAAT/enhancer binding protein) binding site. The results suggest that the overproduction of G-CSFR is at least partly mediated by C/EBPepsilon, whose expression is activated by AML1-MTG8. The ectopic expression of G-CSFR in L-G cells induced cell proliferation in response to G-CSF, but did not inhibit cell differentiation into mature neutrophils. Overexpression of C/EBPepsilon in L-G cells also stimulated G-CSF-dependent cell proliferation. High expression levels of G-CSFR were also found in the leukemic cells of AML patients with t(8;21). Therefore, G-CSF-dependent cell proliferation of myeloid precursor cells may be implicated in leukemogenesis.
t(8;21)易位是与急性髓系白血病（AML）相关的最常见染色体异常之一。在这种易位中，AML1（CBFA2/PEBP2aB）基因被破坏并与MTG8（ETO）基因融合。所得AML1-MTG8融合基因产物在L-G和32Dcl3小鼠髓系前体细胞中的异位表达刺激细胞增殖，而在粒细胞集落刺激因子（G-CSF）作用下不会诱导形态学上向成熟粒细胞的终末分化。本研究发现，AML1-MTG8的异位表达可提高G-CSF受体（G-CSFR）的表达。对G-CSFR基因启动子区域的分析表明，AML1-MTG8对G-CSFR表达的上调不依赖于AML1结合序列，而是依赖于C/EBP（CCAAT/增强子结合蛋白）结合位点。结果表明，G-CSFR的过量产生至少部分由C/EBPε介导，其表达被AML1-MTG8激活。L-G细胞中G-CSFR的异位表达在G-CSF作用下诱导细胞增殖，但不抑制细胞分化为成熟中性粒细胞。L-G细胞中C/EBPε的过表达也刺激了G-CSF依赖性细胞增殖。在t(8;21)的AML患者的白血病细胞中也发现了高表达水平的G-CSFR。因此，髓系前体细胞的G-CSF依赖性细胞增殖可能与白血病发生有关。
