Developmental stage-specific effects of Pim-1 dysregulation on murine bone marrow B cell development.
Developmental stage-specific effects of Pim-1 dysregulation on murine bone marrow B cell development.
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PIM-1失调对鼠骨髓B细胞发育的发育阶段特异性作用。
DOI：
10.1186/s12865-016-0152-1
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发表时间：
2016-06-10
期刊：
影响因子：
3
通讯作者：
Medina KL
中科院分区：
文献类型：
--
作者：
Xu Z;Gwin KA;Li Y;Medina KL
丝氨酸/苏氨酸激酶Pim - 1在造血祖细胞以及B细胞前体的增殖和存活中具有已被证实的作用。Pim - 1是转录因子Hoxa9的一个分子靶点。先前的研究表明，Pim - 1缺陷在表型上模拟了Hoxa9 - / - 小鼠的造血祖细胞缺陷，并且Pim - 1的强制表达使Hoxa9 - / - 造血祖细胞固有的体外增殖缺陷恢复正常。Pim - 1由细胞因子信号诱导，包括早期的淋巴样/B谱系调节因子Flt3和白细胞介素 - 7（IL - 7），并且其表达水平被证明会影响骨髓（BM）中B细胞区室的大小。
在这项研究中，我们试图确定由免疫球蛋白增强子Eμ驱动的Pim - 1转基因表达是否足以挽救Hoxa9或Flt3配体（Flt3l）缺陷小鼠的淋巴样/B细胞前体缺陷。出乎意料的是，Eμ - Pim1的表达加剧了Flt3l - / - 小鼠的淋巴祖细胞缺陷，并且在较小程度上加剧了Hoxa9 - / - 小鼠的淋巴祖细胞缺陷。此外，单独的Eμ - Pim1表达减少了早期的髓系和淋巴系祖细胞，但不影响红系祖细胞。相比之下，Pim - 1缺陷对直至前原B细胞阶段的早期淋巴样/B细胞发育没有显著影响，但导致IgM - B细胞前体显著减少。重要的是，Pim - 1的缺失在淋巴样/早期B细胞祖细胞群上没有模拟出Hoxa9 - 或Flt3l - 缺陷的表型。
这些实验结果表明，Pim - 1的过表达对B淋巴细胞生成和髓细胞生成具有发育阶段特异性的影响。重要的是，这些结果表明Pim - 1缺陷对Hoxa9 - / - 或Flt3l - / - 小鼠的早期淋巴样/B细胞发育缺陷没有显著的促进作用。
The serine threonine kinase Pim-1 has documented roles in hematopoietic progenitor and B cell precursor proliferation and survival. Pim-1 is a molecular target of the transcription factor Hoxa9. Previous studies showed that Pim-1 deficiency phenocopied the hematopoietic progenitor defect in hoxa9-/- mice and forced expression of Pim-1 normalized the in vitro proliferation defect inherent to hoxa9-/- hematopoietic progenitors. Pim-1 is induced by cytokine signaling, including the early lymphoid/B lineage regulators Flt3 and IL-7, and expression levels were shown to influence the size of the B cell compartment in bone marrow (BM). In this study, we sought to determine if transgenic expression of Pim-1, driven by the immunoglobulin enhancer, Eμ, was sufficient to rescue the lymphoid/B cell precursor defect in hoxa9 or flt3-ligand (flt3l) deficient mice. Unexpectedly, expression of Eμ − Pim1 exacerbated lymphoid progenitor deficiencies in flt3l-/-, and to a lesser extent, hoxa9-/- mice. Furthermore, Eμ − Pim1 expression alone reduced early myeloid and lymphoid, but not erythroid, progenitors. In contrast, Pim-1 deficiency had no significant effect on early lymphoid/B cell development through the Pre-Pro-B cell stage, but caused a significant reduction in IgM− B cell precursors. Importantly, loss of Pim-1 did not phenocopy hoxa9- or flt3l-deficiency on the lymphoid/early B cell progenitor pools. These experimental findings demonstrate that Pim-1 overexpression has developmental-stage-specific effects on B lymphopoiesis and myelopoiesis. Importantly, these suggest that Pim-1 deficiency does not contribute significantly to the early lymphoid/B cell developmental deficiency in hoxa9-/- or flt3l-/- mice.