Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77230-1402, USA.
Curr Hematol Malig Rep. 2012 Mar;7(1):26-33. doi: 10.1007/s11899-011-0104-z.
B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), or phosphoinositide 3'-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to "mobilization" of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.
B 细胞受体 (BCR) 信号转导是 B 细胞恶性肿瘤（包括慢性淋巴细胞白血病 [CLL]）的一个中心病理机制，它可促进白血病细胞的存活和增殖，并调节 CLL 细胞的迁移和组织归巢。现在，新型小分子抑制剂可靶向作用于脾酪氨酸激酶 (Syk)、布鲁顿酪氨酸激酶 (Btk) 或磷酸肌醇 3'-激酶 (PI3K) 同工型 p110δ（PI3Kδ），这些抑制剂最近已进入临床阶段，并在 CLL 患者中显示出良好的效果。在治疗的最初几周内，这些药物通常会导致淋巴结病和器官肿大迅速消退，并伴有由于组织驻留的 CLL 细胞“动员”到血液中而导致的淋巴细胞计数短暂激增。然后，在数月的持续治疗后，很大一部分患者会获得缓解。本文综述了 CLL 和其他 B 细胞肿瘤中与 BCR 相关的激酶的关键生物学方面，并对这一令人兴奋的新型激酶抑制剂类药物的未来发展进行了展望。
