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首页> 外文期刊>Molecular and Cellular Biology >Dual Transforming Activities of the FUS (TLS)-ERG Leukemia Fusion Protein Conferred by Two N-Terminal Domains of FUS (TLS)
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Dual Transforming Activities of the FUS (TLS)-ERG Leukemia Fusion Protein Conferred by Two N-Terminal Domains of FUS (TLS)

机译：FUS（TLS）的两个N末端域赋予FUS（TLS）-ERG白血病融合蛋白的双重转化活性

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The FUS (TLS)-ERG chimeric protein associated with t(16;21)(p11;q22) acute myeloid leukemia is structurally similar to the Ewing’s sarcoma chimeric transcription factor EWS-ERG. We found that both FUS-ERG and EWS-ERG could induce anchorage-independent proliferation of the mouse fibroblast cell line NIH 3T3. However, only FUS-ERG was able to inhibit the differentiation into neutrophils of a mouse myeloid precursor cell line L-G and induce its granulocyte colony-stimulating factor-dependent growth. We constructed several deletion mutants of FUS-ERG lacking a part of the N-terminal FUS region. A deletion mutant lacking the region between amino acids 1 and 173 (exons 1 to 5) lost the NIH 3T3-transforming activity but retained the L-G-transforming activity. On the other hand, a mutant lacking the region between amino acids 174 and 265 (exons 6 and 7) lost the L-G-transforming activity but retained the NIH 3T3-transforming activity. These results indicate that the N-terminal region of FUS contains two independent functional domains required for the NIH 3T3 and L-G transformation, which we named TR1 and TR2, respectively. Although EWS intrinsically possessed the TR2 domain, the EWS-ERG construct employed lacked the EWS sequence containing this domain. Since the TR2 domain is always found in chimeric proteins identified from t(16;21) leukemia patients but not in chimeric proteins from Ewing’s sarcoma patients, it seems that the TR2 function is required only for the leukemogenic potential. In addition, we identified three cellular genes whose expression was altered by ectopic expression of FUS-ERG and found that these are regulated in either a TR1-dependent or a TR2-dependent manner. These results suggest that FUS-ERG may activate two independent oncogenic pathways during the leukemogenic process by modulating the expression of two different groups of genes simultaneously.
机译：与t（16; 21）（p11; q22）急性骨髓性白血病相关的FUS（TLS）-ERG嵌合蛋白在结构上与尤因氏肉瘤嵌合转录因子EWS-ERG相似。我们发现FUS-ERG和EWS-ERG均可以诱导小鼠成纤维细胞系NIH 3T3的锚定非依赖性增殖。但是，只有FUS-ERG能够抑制小鼠骨髓前体细胞L-G向中性粒细胞的分化，并诱导其粒细胞集落刺激因子依赖性生长。我们构建了缺少N末端FUS区一部分的FUS-ERG的几个缺失突变体。缺少氨基酸1至173（外显子1至5）之间区域的缺失突变体失去了NIH 3T3转化活性，但保留了L-G转化活性。另一方面，缺少氨基酸174和265之间区域的突变体（外显子6和7）失去了L-G转化活性，但保留了NIH 3T3转化活性。这些结果表明，FUS的N端区域包含NIH 3T3和L-G转化所需的两个独立的功能域，我们分别将其命名为TR1和TR2。尽管EWS本质上具有TR2结构域，但所使用的EWS-ERG构建体缺少包含该结构域的EWS序列。由于TR2结构域总是存在于从t（16; 21）白血病患者中鉴定出的嵌合蛋白中，而不是在尤因氏肉瘤患者中鉴定出的嵌合蛋白中，因此看来TR2功能仅需要潜在的致白血病作用。此外，我们鉴定了三个细胞基因，它们的表达被FUS-ERG的异位表达改变，并发现它们以TR1依赖性或TR2依赖性方式受到调控。这些结果表明，FUS-ERG可通过同时调节两组不同基因的表达，在白血病发生过程中激活两条独立的致癌途径。

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