New roles for B cell receptor associated kinases: when the B cell is not the target
B细胞受体相关激酶的新作用：当B细胞不是靶标时
摘要：
Targeting of B cell receptor associated kinases (BAKs), such as Bruton's tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B cell lymphoma pathogenesis. The functional relevance of BTK for lymphoid malignancies is strongly supported by the observation that resistance to therapy in CLL patients treated with BTK inhibitors such as ibrutinib is often associated with mutations in genes coding for BTK or Phospholipase-C gamma (PLCɣ). In some contrast, next generation sequencing data show that BAKs are mutated at very low frequency in treatment-naïve B cell lymphomas. Therefore, it remains debatable whether BAKs are essential drivers for lymphoma development. In addition, results obtained by targeted deletion of BAKs such as Lyn and Btk in murine CLL models suggest that BAKs may be essential to shape the dialogue between malignant B cells and the tumor microenvironment (TME). Since BAKs are expressed in multiple cell types, BAK inhibitors may disrupt the lymphoma supportive microenvironment. This concept also explains the typical response to BAK inhibitor treatment, characterized by a long-lasting increase of peripheral blood lymphoid cells, due to a redistribution from the lymphoid homing compartments. In addition, BAK inhibitors have shown some efficacy in solid tumors, probably through mediator cells in the TME. This review summarizes and validates the evidence for BAK inhibitors being part of a class of agents that modulate the (hematopoietic) microenvironment of cancers.
通过特异性抑制剂靶向B细胞受体相关激酶（BAK），例如布鲁顿酪氨酸激酶（BTK）或磷酸肌醇-3-激酶（PI3K）δ，已经彻底改变了B淋巴恶性肿瘤的治疗。 BAK是BCR信号传导的关键信号转导物，并且似乎与B细胞淋巴瘤发病机理相关。 BTK对淋巴恶性肿瘤的功能相关性得到以下观察结果的强烈支持：用BTK抑制剂如依鲁替尼治疗的CLL患者对治疗的抗性通常与编码BTK或磷脂酶-Cγ（PLCɣ）的基因突变有关。相比之下，下一代测序数据显示BAK在治疗初始B细胞淋巴瘤中以非常低的频率突变。因此，BAK是否是淋巴瘤发展的重要驱动因素仍存在争议。此外，通过在小鼠CLL模型中靶向缺失诸如Lyn和Btk的BAK获得的结果表明，BAK可能对于形成恶性B细胞和肿瘤微环境（TME）之间的对话是必需的。由于BAK以多种细胞类型表达，BAK抑制剂可破坏淋巴瘤支持性微环境。该概念还解释了对BAK抑制剂治疗的典型反应，其特征在于外周血淋巴样细胞的长期增加，这是由于淋巴归巢隔室的重新分布。此外，BAK抑制剂已经在实体瘤中显示出一些功效，可能通过TME中的介质细胞。本综述总结并验证了BAK抑制剂作为调节癌症（造血）微环境的一类药物的一部分的证据。
B细胞受体相关激酶的新作用：当B细胞不是靶标时
摘要：
Targeting of B cell receptor associated kinases (BAKs), such as Bruton's tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B cell lymphoma pathogenesis. The functional relevance of BTK for lymphoid malignancies is strongly supported by the observation that resistance to therapy in CLL patients treated with BTK inhibitors such as ibrutinib is often associated with mutations in genes coding for BTK or Phospholipase-C gamma (PLCɣ). In some contrast, next generation sequencing data show that BAKs are mutated at very low frequency in treatment-naïve B cell lymphomas. Therefore, it remains debatable whether BAKs are essential drivers for lymphoma development. In addition, results obtained by targeted deletion of BAKs such as Lyn and Btk in murine CLL models suggest that BAKs may be essential to shape the dialogue between malignant B cells and the tumor microenvironment (TME). Since BAKs are expressed in multiple cell types, BAK inhibitors may disrupt the lymphoma supportive microenvironment. This concept also explains the typical response to BAK inhibitor treatment, characterized by a long-lasting increase of peripheral blood lymphoid cells, due to a redistribution from the lymphoid homing compartments. In addition, BAK inhibitors have shown some efficacy in solid tumors, probably through mediator cells in the TME. This review summarizes and validates the evidence for BAK inhibitors being part of a class of agents that modulate the (hematopoietic) microenvironment of cancers.
通过特异性抑制剂靶向B细胞受体相关激酶（BAK），例如布鲁顿酪氨酸激酶（BTK）或磷酸肌醇-3-激酶（PI3K）δ，已经彻底改变了B淋巴恶性肿瘤的治疗。 BAK是BCR信号传导的关键信号转导物，并且似乎与B细胞淋巴瘤发病机理相关。 BTK对淋巴恶性肿瘤的功能相关性得到以下观察结果的强烈支持：用BTK抑制剂如依鲁替尼治疗的CLL患者对治疗的抗性通常与编码BTK或磷脂酶-Cγ（PLCɣ）的基因突变有关。相比之下，下一代测序数据显示BAK在治疗初始B细胞淋巴瘤中以非常低的频率突变。因此，BAK是否是淋巴瘤发展的重要驱动因素仍存在争议。此外，通过在小鼠CLL模型中靶向缺失诸如Lyn和Btk的BAK获得的结果表明，BAK可能对于形成恶性B细胞和肿瘤微环境（TME）之间的对话是必需的。由于BAK以多种细胞类型表达，BAK抑制剂可破坏淋巴瘤支持性微环境。该概念还解释了对BAK抑制剂治疗的典型反应，其特征在于外周血淋巴样细胞的长期增加，这是由于淋巴归巢隔室的重新分布。此外，BAK抑制剂已经在实体瘤中显示出一些功效，可能通过TME中的介质细胞。本综述总结并验证了BAK抑制剂作为调节癌症（造血）微环境的一类药物的一部分的证据。
