The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl
The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl
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DOI：
10.1182/blood.v99.8.2957
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发表时间：
2002-04-15
期刊：
影响因子：
20.3
通讯作者：
Pear, WS
中科院分区：
文献类型：
--
作者：
He, YP;Wertheim, JA;Pear, WS
慢性髓细胞性白血病（CIVIL）中的bcr/abl融合产生了一种嵌合酪氨酸激酶，其性质与完整的c-abl有显著不同。在P210 bcr/abl中，bcr部分包括卷曲螺旋寡聚化结构域（氨基酸1-63）和酪氨酸177（Tyr 177）处的grb 2结合位点，这些位点对成纤维细胞转化至关重要，但在其他细胞系中产生不同的结果。为了研究卷曲螺旋结构域和Tyr 177在促进CIVIL中的作用，构建了4个含有与abl融合的不同bcr结构域的P210 bcr/abi衍生突变体。所有4种突变体，A（1-63）bcr/abl、（1-63）bcr/abi、Tyr 177 Phe bcr/abi和（1-210）bcr/abl均表现出酪氨酸激酶活性升高，并在细胞系中产生因子非依赖性生长。相反，在我们的小鼠模型中，4种突变体的转化潜力存在差异，其中所有接受P210 bcr/abi表达骨髓细胞的小鼠均发生类似于人CIVIL的骨髓增生性疾病（MPD）。在检测的4种突变体中，仅1-210 bcr/abi（包含卷曲螺旋结构域和Tyr 177）诱导MPD。与全长13210不同，该突变体还同时引起B细胞急性淋巴细胞白血病（ALL）。其他3种突变体，Delta（1-63）bcr/abi、Tyr 177 Phe bcr/abi和Delta（1-63）bcr/abi，未能诱导MPD，而是导致T细胞ALL。这些结果表明bcr卷曲螺旋结构域和Tyr 177都是bcr/abl诱导MPD所必需的，并为研究导致CML的下游信号通路提供了基础。（血。2002;99：2957-2968）。(C)2002年，美国血液学会。
The bcr/abl fusion in chronic myelogenous leukemia (CIVIL) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CIVIL, 4 P210 bcr/abi-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, A(1-63) bcr/abl, (1-63) bcr/abi, Tyr177Phe bcr/abi, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abi-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CIVIL. Of the 4 mutants assayed, only 1-210 bcr/abi, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length 13210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, Delta(1-63) bcr/abi, Tyr177Phe bcr/abi, and Delta(1-63) bcr/abi, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML. (Blood. 2002;99:2957-2968). (C) 2002 by The American Society of Hematology.