Human Genetics Foundation, Turin, Italy.
Department of Medical Sciences, University of Turin, Turin, Italy.
Leukemia. 2017 Sep;31(9):1882-1893. doi: 10.1038/leu.2016.383. Epub 2016 Dec 26.
Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.
即使 NOTCH1 在慢性淋巴细胞白血病 (CLL) 中经常发生突变，但其在疾病中的功能影响仍不清楚。使用 CRISPR/Cas9 生成的 Mec-1 细胞系模型，我们表明 NOTCH1 通过调节肿瘤抑制基因 DUSP22 的表达水平来调节 CLL 细胞的生长和归巢。具体来说，NOTCH1 通过调节核复合物影响 DUSP22 启动子的甲基化，从而调节 DNA 甲基转移酶 3A（DNMT3A）的活性。PEST 结构域突变增强了这些影响，稳定了分子并延长了信号转导。具有 NOTCH1 突变克隆的 CLL 患者显示出 DUSP22 水平低和对 CCL19 的趋化活性增强。最后，在异种移植模型中，NOTCH1 突变细胞表现出独特的归巢行为，优先定位于脾脏和大脑。这些发现将 NOTCH1、DUSP22 和 CCL19 驱动的趋化作用连接在一个单一的功能网络中，表明趋化过程的调节可能对与 CLL 中 NOTCH1 突变相关的不利预后有重要贡献。
