Novel Agents and Emerging Strategies for Targeting the B-Cell Receptor Pathway in CLL.
Novel Agents and Emerging Strategies for Targeting the B-Cell Receptor Pathway in CLL.
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DOI：
10.4084/mjhid.2012.067
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发表时间：
2012
影响因子：
3.2
通讯作者：
Laurenti L
中科院分区：
文献类型：
--
作者：
Efremov DG;Wiestner A;Laurenti L
慢性淋巴细胞性白血病（CLL）是恶性CD 5 + B淋巴细胞的疾病，其特征在于自身反应性B细胞受体（BCR）的频繁表达以及增殖和存活对微环境信号的显著依赖。在后者中，通过BCR传播的信号被认为在白血病的发生、维持和演变中发挥关键作用。最近，可以破坏这些信号的药物已成为慢性淋巴细胞白血病的潜在治疗药物，其中一些药物目前正在临床试验中进行评估。激酶SYK、BTK和PI3Kδ抑制剂通过阻断BCR信号转导发挥作用，已获得特别有前景的临床应答。此外，最近的研究集中在磷酸酶PTPN 22，这是参与多种自身免疫性疾病的发病机制，并在CLL细胞中显着过表达，表明它可能在未来开发的策略，将选择性重编程BCR生存信号到信号，诱导白血病细胞死亡。本文综述了这些策略背后的生物学基础，并强调了一些正在进行的临床前和临床研究中最有前途的BCR靶向药物。
Chronic lymphocytic leukemia (CLL) is a disease of malignant CD5+ B lymphocytes that are characterized by frequent expression of autoreactive B-cell receptors (BCRs) and marked dependence on microenvironmental signals for proliferation and survival. Among the latter, signals propagated through the BCR are believed to play a key role in leukemia initiation, maintenance and evolution. Drugs that can disrupt these signals have recently emerged as potential therapeutic agents in CLL and several of them are currently being evaluated in clinical trials. Particularly promising clinical responses have been obtained with inhibitors of the kinases SYK, BTK, and PI3Kδ, which function by blocking BCR signal transduction. In addition, recent studies focusing on the phosphatase PTPN22, which is involved in the pathogenesis of multiple autoimmune diseases and is markedly overexpressed in CLL cells, suggest that it may be possible in the future to develop strategies that will selectively reprogram BCR survival signals into signals that induce leukemic cell death. This review focuses on the biological basis behind these strategies and highlights some of the most promising BCR-targeting agents in ongoing preclinical and clinical studies.