Center of Molecular Biology and Gene Therapy, Department of Internal Medicine- Hematology and Oncology, University Hospital Brno and Medical Faculty, Masaryk University, Brno, Czech Republic.
Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Haematologica. 2018 Feb;103(2):313-324. doi: 10.3324/haematol.2017.178699. Epub 2017 Nov 9.
Chronic lymphocytic leukemia is a disease with up-regulated expression of the transmembrane tyrosine-protein kinase ROR1, a member of the Wnt/planar cell polarity pathway. In this study, we identified COBLL1 as a novel interaction partner of ROR1. shows clear bimodal expression with high levels in chronic lymphocytic leukemia patients with mutated IGHV and approximately 30% of chronic lymphocytic leukemia patients with unmutated IGHV. In the remaining 70% of chronic lymphocytic leukemia patients with unmutated IGHV, expression is low. Importantly, chronic lymphocytic leukemia patients with unmutated IGHV and high have an unfavorable disease course with short overall survival and time to second treatment. serves as an independent molecular marker for overall survival in chronic lymphocytic leukemia patients with unmutated IGHV. In addition, chronic lymphocytic leukemia patients with unmutated IGHV and high show impaired motility and chemotaxis towards CCL19 and CXCL12 as well as enhanced B-cell receptor signaling pathway activation demonstrated by increased PLCγ2 and SYK phosphorylation after IgM stimulation. expression also changes during B-cell maturation in non-malignant secondary lymphoid tissue with a higher expression in germinal center B cells than naïve and memory B cells. Our data thus suggest involvement not only in chronic lymphocytic leukemia but also in B-cell development. In summary, we show that expression of , encoding novel ROR1-binding partner, defines chronic lymphocytic leukemia subgroups with a distinct response to microenvironmental stimuli, and independently predicts survival of chronic lymphocytic leukemia with unmutated IGHV.
慢性淋巴细胞白血病是一种膜酪氨酸蛋白激酶 ROR1 表达上调的疾病，ROR1 是 Wnt/平面细胞极性途径的成员。在这项研究中，我们鉴定了 COBLL1 是 ROR1 的一个新的相互作用伙伴。COBLL1 表现出明显的双峰表达，在IGHV 突变的慢性淋巴细胞白血病患者中高水平表达，约 30%的 IGHV 未突变的慢性淋巴细胞白血病患者中表达。在其余 70%的 IGHV 未突变的慢性淋巴细胞白血病患者中，COBLL1 的表达水平较低。重要的是，IGHV 未突变且 COBLL1 高表达的慢性淋巴细胞白血病患者疾病进程不良，总生存期和第二次治疗时间均较短。COBLL1 是 IGHV 未突变的慢性淋巴细胞白血病患者总生存期的独立分子标志物。此外，IGHV 未突变且 COBLL1 高表达的慢性淋巴细胞白血病患者的迁移和趋化性受损，对 CCL19 和 CXCL12 的趋化性降低，以及 IgM 刺激后 PLCγ2 和 SYK 磷酸化增加，表明 B 细胞受体信号通路激活增强。COBLL1 在非恶性次级淋巴组织的 B 细胞成熟过程中表达也发生变化，在生发中心 B 细胞中的表达高于幼稚 B 细胞和记忆 B 细胞。我们的数据表明，COBLL1 的表达不仅参与慢性淋巴细胞白血病，而且参与 B 细胞发育。总之，我们表明，编码新型 ROR1 结合伙伴的 COBLL1 的表达定义了对微环境刺激具有不同反应的慢性淋巴细胞白血病亚群，并且独立预测 IGHV 未突变的慢性淋巴细胞白血病的生存。
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