Kil Laurens P, de Bruijn Marjolein Jw, van Hulst Jennifer Ac, Langerak Anton W, Yuvaraj Saravanan, Hendriks Rudi W
Department of Pulmonary Medicine, Erasmus MC Rotterdam, The Netherlands.
Am J Blood Res. 2013;3(1):71-83. Epub 2013 Jan 17.
In chronic lymphocytic leukemia (CLL) signals from the B cell receptor (BCR) play a major role in disease development and progression. In this light, new therapies that specifically target signaling molecules downstream of the BCR continue to be developed. While first studies on the selective small molecule inhibitor of Bruton's tyrosine kinase (Btk), Ibrutinib (PCI-32765), demonstrated that Btk inhibition sensitizes CLL cells to apoptosis and alters their migratory behavior, these studies however did not address whether Btk-mediated signaling is involved in the process of CLL leukemogenesis. To investigate the requirement of Btk signaling for CLL development, we modulated Btk expression in the IgH.ETμ CLL mouse model, which is based on sporadic expression of the simian oncovirus SV40 T-antigen in mature B cells. To this end, we crossed IgH.ETμ mice on a Btk-deficient background or introduced a human Btk transgene (CD19-hBtk). Here we show that Btk deficiency fully abrogates CLL formation in IgH.ETμ mice, and that leukemias formed in Btk haplo-insufficient mice selectively expressed the wild-type Btk allele on their active X chromosome. Conversely, Btk overexpression accelerated CLL onset, increased mortality, and was associated with selection of non-stereotypical BCRs into CLL clones. Taken together, these data show that Btk expression represents an absolute prerequisite for CLL development and that Btk mediated signaling enhances leukemogenesis in mice. We therefore conclude that in CLL Btk expression levels set the threshold for malignant transformation.
在慢性淋巴细胞白血病（CLL）中，来自B细胞受体（BCR）的信号在疾病发展和进程中起主要作用。鉴于此，继续研发特异性靶向BCR下游信号分子的新疗法。虽然对布鲁顿酪氨酸激酶（Btk）的选择性小分子抑制剂依鲁替尼（PCI-32765）的初步研究表明，抑制Btk可使CLL细胞对凋亡敏感并改变其迁移行为，但这些研究并未探讨Btk介导的信号传导是否参与CLL白血病发生过程。为了研究Btk信号传导对CLL发展的必要性，我们在基于猿猴病毒SV40 T抗原在成熟B细胞中散在表达的IgH.ETμ CLL小鼠模型中调节Btk表达。为此，我们将IgH.ETμ小鼠与Btk缺陷背景的小鼠杂交，或导入人Btk转基因（CD19-hBtk）。在此我们表明，Btk缺陷完全消除了IgH.ETμ小鼠中的CLL形成，并且在Btk单倍体不足小鼠中形成的白血病在其活跃的X染色体上选择性表达野生型Btk等位基因。相反，Btk过表达加速了CLL发病，增加了死亡率，并且与非典型BCR被选入CLL克隆有关。综上所述，这些数据表明Btk表达是CLL发展的绝对先决条件，并且Btk介导的信号传导增强了小鼠的白血病发生。因此我们得出结论，在CLL中，Btk表达水平设定了恶性转化的阈值。
