EBF1-JAK2 inhibits the PAX5 function through physical interaction with PAX5 and kinase activity.
EBF1-JAK2 inhibits the PAX5 function through physical interaction with PAX5 and kinase activity.
复制标题
EBF1-JAK2 通过与 PAX5 的物理相互作用和激酶活性来抑制 PAX5 功能。
DOI：
10.1007/s12185-023-03585-z
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
et al.
中科院分区：
文献类型：
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作者：
Kojima Y;Kawashima F;Yasuda T;et al.
B细胞急性淋巴细胞白血病（B-ALL）中经常发现B细胞调节因子和生长信号成分（例如JAK-STAT途径）的基因异常。EBF 1是一种B细胞调节因子，它调节PAX 5的表达，并与PAX 5共同调节B细胞分化。本研究对EBF 1和JAK 2融合蛋白EBF 1-JAK 2（E-J）的功能进行了初步分析。E-J引起JAK-STAT和MAPK通路的组成性激活，并诱导依赖于精氨酸的细胞系中的自主细胞生长。E-J不影响EBF 1的转录活性，但抑制PAX 5的转录活性。E-J与PAX 5的物理相互作用和E-J的激酶活性都是E-J抑制PAX 5功能所必需的，尽管抑制的详细机制尚不清楚。重要的是，使用我们先前对323例原发性BCR-ABL 1阴性ALL样本的RNA-seq数据进行的基因集富集分析表明，E-J阳性ALL细胞中PAX 5的转录靶基因受到抑制，这表明E-J也抑制了ALL细胞中PAX 5的功能。我们的研究结果揭示了激酶融合蛋白阻断分化的机制。
Gene aberrations of B-cell regulators and growth signal components such as the JAK–STAT pathway are frequently found in B-cell acute lymphoblastic leukemia (B-ALL). EBF1 is a B-cell regulator that regulates the expression of PAX5 and co-operates with PAX5 to regulate B-cell differentiation. Here, we analyzed the function of the fusion protein of EBF1 and JAK2, EBF1–JAK2 (E–J). E–J caused constitutive activation of JAK–STAT and MAPK pathways and induced autonomous cell growth in a cytokine-dependent cell line. E–J did not affect the transcriptional activity of EBF1 but inhibited that of PAX5. Both the physical interaction of E–J with PAX5 and kinase activity of E–J were required for E–J to inhibit PAX5 function, although the detailed mechanism of inhibition remains unclear. Importantly, gene set enrichment analysis using the results of our previous RNA-seq data of 323 primary BCR-ABL1-negative ALL samples demonstrated repression of the transcriptional target genes of PAX5 inE–J-positive ALL cells, which suggests that E–J also inhibited PAX5 function in ALL cells. Our results shed new light on the mechanisms of differentiation block by kinase fusion proteins.