A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.
A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.
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DOI：
10.1158/0008-5472.can-10-0607
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发表时间：
2010-09-15
期刊：
影响因子：
11.2
通讯作者：
Druker BJ
中科院分区：
文献类型：
--
作者：
Seo JH;Wood LJ;Agarwal A;O'Hare T;Elsea CR;Griswold IJ;Deininger MW;Imamoto A;Druker BJ
CRKL（CRK样）是一种衔接蛋白，在表达酪氨酸激酶p210 BCR-ABL的细胞中主要磷酸化，p210 BCR-ABL是导致慢性粒细胞白血病（CML）的（9;22）染色体易位的融合产物。然而，CRKL是否在p210 BCR-ABL转化中发挥功能性作用尚不清楚。在这里，我们表明p210 BCR-ABL需要CRKL来支持骨髓祖细胞的IL-3非依赖性生长和来自胎肝来源的造血祖细胞的B淋巴细胞的长期生长。此外，以高亲和力结合CRKL SH 2结构域的合成磷酸酪氨酰肽阻断内源性CRKL与p210 BCR-ABL复合物的结合，并降低K562人白血病细胞以及由p210 BCR-ABL或伊马替尼耐药突变体T315 I转化的小鼠造血细胞中的c-MYC水平。这些结果表明，CRKL作为衔接蛋白的功能是必不可少的p210 BCR-ABL诱导转化。
CRKL (CRK-Like) is an adapter protein predominantly phosphorylated in cells that express the tyrosine kinase p210BCR-ABL, the fusion product of a (9;22) chromosomal translocation causative for chronic myeloid leukemia (CML). It has been unclear, however, whether CRKL plays a functional role in p210BCR-ABL transformation. Here we show that CRKL is required for p210BCR-ABL to support IL-3-independent growth of myeloid progenitor cells and long-term outgrowth of B-lymphoid cells from fetal liver-derived hematopoietic progenitor cells. Furthermore, a synthetic phosphotyrosyl peptide that binds to the CRKL SH2 domain with high affinity blocks association of endogenous CRKL with the p210BCR-ABL complex and reduces c-MYC levels in K562 human leukemic cells as well as mouse hematopoietic cells transformed by p210BCR-ABL or the imatinib-resistant mutant T315I. These results indicate that the function of CRKL as an adapter protein is essential for p210BCR-ABL-induced transformation.