西亚试剂：过量BCR信号传导的抗癌作用

Markus Müschen 及同事分析，在某些具有组成性 “B细胞受体”(BCR)信号传导的B细胞恶性肿瘤(携带BCR-ABL转位的“急性淋巴细胞白血病”)中，也许有可能通过一个中等水平的BCR信号传导来改变有利于B细胞的正常选择过程，反而来驱动BCR信号传导水平超过一个阈限，在这个阈限之上，恶性B细胞就无法存活了。他们显示，这一点在一个小鼠模型中比如说就可以通过激酶SYK的超活化做到。在该小鼠模型中，一个SYK通道的药理活化可以抑制来自患者的肿瘤异种移植物的生长。这一概念与寻求阻断BCR信号传导的B淋巴瘤治疗方法截然不同，也许值得在临床上进行探索。B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR)1 or hyperactivation above maximum (for example, self-reactive BCR)2, 3 thresholds of signalling strength causes negative selection. In ~25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling4,5. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival6. We tested the hypothesis that targeted hyperactivation—above a maximum threshold—will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR–ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a andLair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1)9, we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL.

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