Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models
Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models
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DOI：
10.1182/blood-2008-06-164368
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发表时间：
2009-03-19
期刊：
影响因子：
20.3
通讯作者：
Mercher, Thomas
中科院分区：
文献类型：
--
作者：
Cornejo, Melanie G.;Kharas, Michael G.;Mercher, Thomas
酪氨酸激酶 JAK3 在正常淋巴细胞发育过程中发挥着明确的作用，并且在多种淋巴恶性肿瘤中被组成型磷酸化。然而，它对淋巴瘤发生的贡献仍然难以捉摸。在本研究中，我们使用新发现的激活性 JAK3A572V 突变来阐明组成型 JAK3 信号传导对小鼠淋巴细胞生成的影响。在骨髓移植模型中，JAK3A572V 诱导一种侵袭性、致命性和可移植的淋巴增殖性疾病，其特征是 CD8(+)TCR α beta(+)CD44(+)CD122(+)Ly-6C(+) T 细胞的扩增，与效应/记忆 T 细胞亚型非常相似。与野生型对应物相比，这些细胞对多克隆刺激的反应显示出更高的增殖能力，随着Bcl-2表达的升高而提高存活率，并增加干扰素γ（IFNγ）和肿瘤坏死因子α（TNFα）的产生，这与针对同种异体靶细胞的细胞毒能力增强相关。有趣的是，JAK3A572V 疾病是亲表皮性的，会产生表皮内微脓肿。总而言之，这些临床特征让人想起在罕见但具有侵袭性的 CD8+ 人皮肤 T 细胞淋巴瘤 (CTCL) 亚型中观察到的临床特征。然而，当细胞移植到 MHC-I 缺陷的背景中时，我们也观察到 CD4(+) CTCL 样表型。这些数据表明，JAK3 的组成型激活会破坏 T 细胞稳态并诱发小鼠淋巴增殖性疾病。 （血。2009；113：2746-2754）
The tyrosine kinase JAK3 plays a well-established role during normal lymphocyte development and is constitutively phosphorylated in several lymphoid malignancies. However, its contribution to lymphomagenesis remains elusive. In this study, we used the newly identified activating JAK3A572V mutation to elucidate the effect of constitutive JAK3 signaling on murine lymphopoiesis. In a bone marrow transplantation model, JAK3A572V induces an aggressive, fatal, and transplantable lymphoproliferative disorder characterized by the expansion of CD8(+)TCR alpha beta(+)CD44(+)CD122(+)Ly-6C(+) T cells that closely resemble an effector/memory T-cell subtype. Compared with wild-type counterparts, these cells show increased proliferative capacities in response to polyclonal stimulation, enhanced survival rates with elevated expression of Bcl-2, and increased production of interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha), correlating with enhanced cytotoxic abilities against allogeneic target cells. Of interest, the JAK3A572V disease is epidermotropic and produces intraepidermal microabscesses. Taken together, these clinical features are reminiscent of those observed in an uncommon but aggressive subset of CD8(+) human cutaneous T-cell lymphomas (CTCLs). However, we also observed a CD4(+) CTCL-like phenotype when cells are transplanted in an MHC-I-deficient background. These data demonstrate that constitutive JAK3 activation disrupts T-cell homeostasis and induces lymphoproliferative diseases in mice. (Blood. 2009;113:2746-2754)