Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice.
Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice.
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DOI：
10.1182/blood.2020004996
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发表时间：
2020-09
期刊：
影响因子：
20.3
通讯作者：
Javier Raboso-Gallego;Ana Casado-García;Xiaoyu Jiang;Marta Isidro-Hernández;A. Gentles;Shuchun Zhao;Y. Natkunam;O. Blanco;Verónica Domínguez;Belén Pintado;D. Alonso-López;J De Las Rivas;Carolina Vicente-Dueñas;I. Lossos;I. Sánchez-García
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文献类型：
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作者：
Javier Raboso-Gallego;Ana Casado-García;Xiaoyu Jiang;Marta Isidro-Hernández;A. Gentles;Shuchun Zhao;Y. Natkunam;O. Blanco;Verónica Domínguez;Belén Pintado;D. Alonso-López;J De Las Rivas;Carolina Vicente-Dueñas;I. Lossos;I. Sánchez-García
弥漫性大B细胞淋巴瘤（DLBCL）是临床和遗传异质性肿瘤。B细胞特异性的多种生物学过程的失调，例如B细胞受体（BCR）信号传导和运动调节，有助于淋巴瘤发生。HGAL是控制BCR信号传导和B淋巴细胞运动的B细胞特异性衔接蛋白。在正常B细胞中，它在Germinant Center（GC）B淋巴细胞中表达，并在进一步分化时迅速下调。大多数DLBCL肿瘤，主要是GC B细胞，但也有活化型，表达HGAL。为了研究HGAL在体内组成型表达的后果，我们使用三种不同的限制性Cre介导的方法分别在造血干细胞（HSC）、pro-B细胞或GC B细胞中启动HGAL的表达，产生了在造血发育的不同阶段条件性表达人HGAL的小鼠。免疫刺激后，我们在小鼠中观察到较大的GC，其中HGAL表达在GC B细胞中启动。所有三种小鼠品系从13个月大开始以12-30%的频率发展DLBCL，导致存活期较短。免疫组化研究表明，所有分析的肿瘤GC B细胞型。外显子测序证实了人DLBCL中报告的突变。我们的数据表明，组成型HGAL的强制表达导致DLBCL的发展。
Diffuse large B cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B-cells, such as B cell receptor (BCR) signaling and motility regulation contribute to lymphomagenesis. HGAL is a B-cell specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B-cells it is expressed in Germinal Center (GC) B lymphocytes and promptly downregulated upon further differentiation. Majority of DLBCL tumors, mainly GC B-cell but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express the human HGAL at different stages of hematopoietic development using three different restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells (HSC), pro-B cells or GC B-cells, respectively. Following immune stimulation, we observed larger GCs in mice where HGAL expression was initiated in GC B-cells. All three mouse strains developed DLBCL at a frequency of 12-30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing demonstrated mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.