ASK1 promotes apoptosis of normal and malignant plasma cells
ASK1 promotes apoptosis of normal and malignant plasma cells
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DOI：
10.1182/blood-2011-12-399808
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发表时间：
2012-08-02
期刊：
影响因子：
20.3
通讯作者：
Lin, Kuo-I
中科院分区：
文献类型：
--
作者：
Lin, Fan-Ru;Huang, Shang-Yi;Lin, Kuo-I
尽管伴随免疫反应的短期浆细胞过度产生免疫球蛋白与它们的凋亡有关，但在这一背景下，长寿命的浆细胞如何适应以确保其寿命尚不清楚。在这里，我们证明了凋亡信号调节激酶1(ASK1)有助于浆细胞的凋亡，因为ASK1活性是在短暂的浆细胞分化过程中被诱导的，并且当ASK1缺陷小鼠产生这些细胞时，这些细胞比对照组小鼠存活得更好。此外，免疫产生的抗原特异性长寿命浆细胞在ASK1缺陷小鼠中积累，表明ASK1对长寿命浆细胞的存活也起到负面作用。在恶性浆细胞中，ASK1的转录被B淋巴细胞诱导成熟蛋白-1(Blimp-1)直接抑制。ASK1和Blimp-1在正常人成熟B细胞和多发性骨髓瘤(MM)患者骨髓浆细胞中的表达呈负相关。抑制ASK1对细胞存活至关重要，因为ASK1在MM细胞中的强制表达在体外会导致细胞凋亡，并降低异种移植动物模型中的MM负荷；此外，ASK1活性的改变会影响MM细胞的存活。我们的发现表明了ASK1调节正常和恶性浆细胞存活的新机制。(血。2012；120(5)：1039-1047)
Although the overproduction of immunoglobulins by short-lived plasma cells accompanying an immune response links with their apoptosis, how long-lived plasma cells adapt to ensure their longevity in this context is obscure. Here, we show that apoptosis signal-regulating kinase 1 (ASK1) contributes to apoptosis of plasma cells because ASK1 activity was induced during differentiation of short-lived plasma cells, and, when produced by ASK1-deficient mice, these cells survived better than those of control mice. Moreover, antigen-specific long-lived plasma cells generated by immunization accumulated in ASK1-deficient mice, suggesting ASK1 also plays a negative role in survival of long-lived plasma cells. In malignant plasma cells, ASK1 transcription was directly suppressed by B lymphocyte-induced maturation protein-1 (Blimp-1). The expression of ASK1 and Blimp-1 showed an inverse correlation between normal human mature B cells and bone marrow plasma cells from patients with multiple myeloma (MM). Suppression of ASK1 is crucial for cell survival because its enforced expression in MM cells caused apoptosis in vitro and lowered MM load in a xenograft animal model; furthermore, alteration of ASK1 activity affected MM cell survival. Our findings indicate a novel mechanism underlying the regulation of survival in normal and malignant plasma cells by ASK1. (Blood. 2012;120(5):1039-1047)