TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ
TC-PTP-deficient bone marrow stromal cells fail to support normal B lymphopoiesis due to abnormal secretion of interferon-γ
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DOI：
10.1182/blood-2006-08-044370
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发表时间：
2007-05-15
期刊：
影响因子：
20.3
通讯作者：
Tremblay, Michel L.
中科院分区：
文献类型：
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作者：
Bourdeau, Annie;Dube, Nadia;Tremblay, Michel L.
T细胞蛋白酪氨酸磷酸酶(TC-PTP)是JAK/STAT细胞因子信号通路的负调控因子。我们的研究表明，缺乏TC-PTP会导致早期骨髓B细胞缺陷，其特征是前B细胞向未成熟B细胞阶段的转变受阻。这种表型是B细胞固有的，但最重要的是由于骨髓基质的异常。我们发现TC-PTP-/-小鼠的骨髓基质细胞具有分泌232-890pg/mL干扰素的独特特性。这些高水平的干扰素-γ导致对IL-7刺激TC-PTP-/-Pre-B细胞的有丝分裂指数降低2倍，并降低了Jak/Stat信号分子下游IL-7受体的反应性。此外，我们注意到这些前B细胞中STAT1的组成性磷酸化，并证明这是由于TC-PTP-/-骨髓基质细胞分泌的可溶性干扰素-γ所致。有趣的是，在TC-PTP缺乏的骨髓基质环境中培养小鼠早期Pre-B白血病细胞会导致这些恶性细胞的凋亡率增加40%。我们的结果揭示了TC-PTP在正常B淋巴细胞生成中的新作用，并提示调节骨髓微环境是选择性B细胞白血病的一种潜在治疗途径。
The T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of the Jak/Stat cytokine signaling pathway. Our study shows that the absence of TC-PTP leads to an early bone marrow B-cell deficiency characterized by hindered transition from the pre-B cell to immature B-cell stage. This phenotype is intrinsic to the B cells but most importantly due to bone marrow stroma abnormalities. We found that bone marrow stromal cells from TC-PTP-/- mice have the unique property of secreting 232-890 pg/mL IFN-gamma. These high levels of IFN-gamma result in 2-fold reduction in mitotic index on IL-7 stimulation of TC-PTP-/- pre-B cells and lower responsiveness of IL-7 receptor downstream Jak/Stat signaling molecules. Moreover, we noted constitutive phosphorylation of Stat1 in those pre-B cells and demonstrated that this was due to soluble IFN-gamma secreted by TC-PTP-/- bone marrow stromal cells. Interestingly, culturing murine early pre-B leukemic cells within a TC-PTP-deficient bone marrow stroma environment leads to a 40% increase in apoptosis in these malignant cells. Our results unraveled a new role for TC-PTP in normal B lymphopoiesis and suggest that modulation of bone marrow microenvironment is a potential therapeutic approach for selected B-cell leukemia.