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 in E–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.

B 细胞调节因子和生长信号成分（例如 JAK-STAT 通路）的基因畸变常见于 B 细胞急性淋巴细胞白血病 (B-ALL)。EBF1是B细胞调节因子，调节PAX5的表达并与PAX5协同调节B细胞分化。在这里，我们分析了 EBF1 和 JAK2 的融合蛋白 EBF1–JAK2 (E–J) 的功能。E-J 引起 JAK-STAT 和 MAPK 通路的组成型激活，并诱导细胞因子依赖性细胞系的自主细胞生长。E-J不影响EBF1的转录活性，但抑制PAX5的转录活性。E-J 与 PAX5 的物理相互作用以及 E-J 的激酶活性都是 E-J 抑制 PAX5 功能所必需的，尽管详细的抑制机制仍不清楚。重要的，E-J阳性 ALL 细胞，这表明 E-J 也抑制 ALL 细胞中的 PAX5 功能。我们的结果为激酶融合蛋白的分化阻断机制提供了新的线索。