PU.1 Opposes IL-7-Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase
PU.1 Opposes IL-7-Dependent Proliferation of Developing B Cells with Involvement of the Direct Target Gene Bruton Tyrosine Kinase
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DOI：
10.4049/jimmunol.1401569
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发表时间：
2015-01-15
影响因子：
4.4
通讯作者：
DeKoter, Rodney P.
中科院分区：
文献类型：
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作者：
Christie, Darah A.;Xu, Li S.;DeKoter, Rodney P.
B细胞（CD 19-Cre Delta PB小鼠）中编码E26转化特异性转录因子PU. 1和Spi-B的基因缺失导致B细胞发育受损，随后发生B细胞急性淋巴细胞白血病，发生率为100%，中位生存期为21周。然而，对解释这些小鼠白血病发生的靶基因知之甚少。在这项研究中，我们发现，未成熟的B细胞的发生频率在白血病前CD 19-Cre Delta PB小鼠的骨髓中改变。来自CD 19-Cre Delta PB小鼠的富集的pro-B细胞在移植后诱导疾病，表明这些是白血病起始细胞。来自白血病前CD 19-Cre Delta PB小鼠的骨髓细胞对IL-7的反应性增加，并且可以响应于这种细胞因子而无限增殖。与对照组相比，白血病前和白血病CD 19-Cre Delta PB细胞中IL-7信号负调节因子布鲁顿酪氨酸激酶（BTK）减少。在培养的CD 19-Cre Delta PB pro-B细胞系中诱导PU. 1表达诱导Btk表达，随后减少STAT 5磷酸化和早期凋亡。染色质免疫沉淀分析表明，PU.1和Spi-B直接调节Btk。BTK的异位表达足以诱导培养的pro-B细胞的凋亡。总之，这些结果表明PU. 1和Spi-B激活Btk以对抗发育中的B细胞中的IL-7应答性。
Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-Cre Delta PB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-Cre Delta PB mice. Enriched pro-B cells from CD19-Cre Delta PB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-Cre Delta PB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-Cre Delta PB cells compared with controls. Induction of PU.1 expression in cultured CD19-Cre Delta PB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells.