Chen Zhengshan, Shojaee Seyedmehdi, Buchner Maike, Geng Huimin, Lee Jae Woong, Klemm Lars, Titz Björn, Graeber Thomas G, Park Eugene, Tan Ying Xim, Satterthwaite Anne, Paietta Elisabeth, Hunger Stephen P, Willman Cheryl L, Melnick Ari, Loh Mignon L, Jung Jae U, Coligan John E, Bolland Silvia, Mak Tak W, Limnander Andre, Jumaa Hassan, Reth Michael, Weiss Arthur, Lowell Clifford A, Müschen Markus
Department of Laboratory Medicine, University of California, San Francisco, California 94143, USA.
Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095, USA.
Nature. 2015 May 21;521(7552):357-61. doi: 10.1038/nature14231. Epub 2015 Mar 23.
B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) 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 signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. 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 and Lair1 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), 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.
B细胞会被选择为具有中等水平的B细胞抗原受体（BCR）信号强度：信号强度衰减至最低水平以下（例如，无功能的BCR）或超激活至最高水平以上（例如，自身反应性BCR）都会导致阴性选择。在约25%的病例中，急性淋巴细胞白血病（ALL）细胞携带致癌性BCR-ABL1酪氨酸激酶（费城染色体阳性），其模拟组成型激活的前BCR信号。目前的治疗方法主要集中在开发更有效的酪氨酸激酶抑制剂，以将致癌信号抑制在生存所需的最低阈值以下。我们测试了这样一个假设，即靶向超激活——超过最高阈值——将启动一个删除检查点以清除自身反应性B细胞，并选择性杀死ALL细胞。在这里，我们通过测试小鼠BCR-ABL1细胞中近端前BCR信号的各种成分发现，Syk酪氨酸激酶活性的逐步增加是诱导细胞死亡所必需且足够的。超活性Syk在功能上等同于ALL细胞上自身反应性BCR的急性激活。尽管发生了致癌转化，但这种阴性选择的基本机制在ALL细胞中仍然起作用。与正常前B细胞不同，来自患者的ALL细胞高水平表达抑制性受体PECAM1、CD300A和LAIR1。遗传学研究表明，Pecam1、Cd300a和Lair1对于通过募集抑制性磷酸酶Ptpn6（参考文献7）和Inpp5d（参考文献8）来校准致癌信号强度至关重要。使用一种新型的INPP5D（也称为SHIP1）小分子抑制剂，我们证明SYK的药理学超激活和阴性B细胞选择的参与代表了一种有前景的新策略，可克服人类ALL中的耐药性。
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