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ENGLISH ABSTRACT
布鲁顿酪氨酸激酶抑制剂治疗华氏巨球蛋白血症的研究进展
张睿
吴涛
周芮
作者及单位信息
·
DOI： 10.3760/cma.j.cn231536-20241009-00085
Progress of Bruton’s tyrosine kinase inhibitors in the treatment of Waldenström Macroglobulinemia
Zhang Rui
Wu Tao
Zhou Rui
Authors Info & Affiliations
Zhang Rui
Department of Hematology, Center for Hematologic Diseases of Chinese PLA, the 940th Hospital of Joint Logistics Support force of Chinese People’s Liberation Army (Lanzhou Military Command General Hospital), Lanzhou 730050, China
Wu Tao
Department of Hematology, Center for Hematologic Diseases of Chinese PLA, the 940th Hospital of Joint Logistics Support force of Chinese People’s Liberation Army (Lanzhou Military Command General Hospital), Lanzhou 730050, China
Zhou Rui
Department of Hematology, Center for Hematologic Diseases of Chinese PLA, the 940th Hospital of Joint Logistics Support force of Chinese People’s Liberation Army (Lanzhou Military Command General Hospital), Lanzhou 730050, China
·
DOI： 10.3760/cma.j.cn231536-20241009-00085
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摘要

华氏巨球蛋白血症(Waldenström macroglobulinemia, WM)是一种罕见的惰性淋巴浆细胞性淋巴瘤，主要以淋巴浆细胞浸润骨髓和高表达单克隆免疫球蛋白M(immunoglobulin, IgM)为特征。布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase, BTK)属于非受体蛋白酪氨酸激酶Tec家族的成员之一，是B细胞受体信号通路的关键激酶，对B细胞的发育和存活至关重要。近年来，随着分子生物学研究的深入和药物研发的进步，BTK抑制剂在治疗WM中展现出显著疗效，为WM患者提供了新的治疗选择。本文就BTK在WM发病中的作用机制、BTK抑制剂治疗WM的研究进展进行综述。

华氏巨球蛋白血症;布鲁顿酪氨酸激酶;BTK抑制剂;治疗策略
ABSTRACT

Waldenström macroglobulinemia (WM) is a rare inert lymphoplasmacytic lymphoma characterized primarily by lymphoplasmacytic infiltration of bone marrow and high expression of monoclonal immunoglobulin M (IgM). Bruton’s Tyrosine Kinase (BTK), a member of the Tec family of non-receptor protein tyrosine kinases, is a key kinase in the B-cell receptor signaling pathway and is essential for B-cell development and survival. In recent years, with the deepening of molecular biology research and the advancement of drug development, BTK inhibitors have demonstrated significant efficacy in the treatment of WM, providing new therapeutic options for WM patients. This article reviews the mechanism of action of BTK in the pathogenesis of WM and the research progress of BTK inhibitors in the treatment of WM.

Waldenström macroglobulinemia;Bruton’s Tyrosine Kinase;BTK inhibitors;Therapeutic strategies
Wu Tao, Email: tendef.habaeynehzoatuw
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引用本文

张睿,吴涛,周芮. 布鲁顿酪氨酸激酶抑制剂治疗华氏巨球蛋白血症的研究进展[J]. 国际遗传学杂志,2025,48(01)：38-44.

DOI:10.3760/cma.j.cn231536-20241009-00085

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华氏巨球蛋白血症(Waldenström macroglobulinemia, WM)是一种罕见的惰性淋巴组织增生性恶性肿瘤，其特征是多形性的B淋巴细胞(包括浆细胞)与血清中高含量的单克隆免疫球蛋白M(immunoglobulin, IgM) [ 1 , 2 ]，目前全基因组测序已确定 MYD88和 CXCR4基因突变均为诱导WM发生的常见突变基因。其中， MYD88 L265P与 MYD88野生型突变基因相比，具有更高的血清IgM水平、血液高黏滞度和更严重的骨髓受累程度 [ 3 ]。另外，研究表明WM患者CXCR4编码区存在40多种不同的突变，最常见的是C1013G/A突变，使其临床病程更具侵袭性 [ 4 , 5 ]。研究显示，布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase, BTK)对B细胞的发育和存活至关重要，属于Tec家族酪氨酸激酶的成员之一，是B细胞恶性肿瘤发生发展的关键参与者 [ 6 , 7 , 8 ]。B细胞受体激活后生成的磷脂酰肌醇-3, 4, 5-三磷酸(phosphatidylinositol-3, 4, 5- trisphosphate, PIP3)可将BTK募集到B细胞受体复合物中，然后BTK被Src家族激酶磷酸化；活化成BTK磷酸化磷脂酶C-γ2,后进一步活化蛋白激酶C,最后活化核因子κB;核因子κ B诱导 BTK基因进一步转录从而诱导凋亡抑制 [ 9 , 10 , 11 ]。研究发现约有90%～95%的WM患者存在MYD88的L265P突变，这一突变可导致BTK活化，活化后的BTK可激活B细胞中的重要蛋白质即核因子κB，进而提高WM细胞的存活率 [ 10 , 12 ]。因此，MYD88 L265P成为BTK抑制剂的潜在有效突变靶点，本文就BTK在WM发病中的作用机制、BTK抑制剂治疗WM的研究进展进行综述。
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