Institute for Molecular Medicine, University Medical Centre of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Department of Infection and Immunity, Luxembourg Institute of Health, Strassen, Luxembourg.
Leukemia. 2018 Jan;32(1):72-82. doi: 10.1038/leu.2017.168. Epub 2017 Jun 1.
The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-κB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-κB and tumor suppressor gene CYLD regulates the pool of CD5 B cells through sustained canonical NF-κB signaling. Reinforced canonical NF-κB activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5 B cells, highly reminiscent of human B-CLL. We show that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination-driven canonical NF-κB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-κB-driven clonal CD5 B-cell expansion and ultimately CLL-like disease.
慢性淋巴细胞白血病（CLL）的发病机制与 NF-κB 的组成性激活有关，但潜在机制尚不清楚。在这里，我们显示 NF-κB 和肿瘤抑制基因 CYLD 的负调节剂的选择性剪接通过持续的经典 NF-κB 信号调节 CD5 B 细胞池。增强的经典 NF-κB 活性通过促进 CD5 B 细胞的存活和增殖导致衰老小鼠中 B1 细胞相关肿瘤的形成，这非常类似于人类 B-CLL。我们表明，相当数量的 CLL 患者样本表达 sCYLD，强烈暗示其在人类 B-CLL 中起作用。我们提出，我们的新型 CLL 样小鼠模型代表了研究 CLL 中泛素化驱动的经典 NF-κB 激活的合适工具。因此，抑制这种负调节剂的选择性剪接对于防止 NF-κB 驱动的克隆 CD5 B 细胞扩增并最终导致 CLL 样疾病是必不可少的。
