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NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways.
Leukemia ( IF 11.4 ) Pub Date : 2018-Mar-01 , DOI: 10.1038/leu.2017.296
D Benedetti , E Tissino , F Pozzo , T Bittolo , C Caldana , C Perini , D Martorelli , V Bravin , T D’Agaro , F M Rossi , R Bomben , E Santinelli , F Zaja , G Pozzato , A Chiarenza , F Di Raimondo , G Del Poeta , D Rossi , G Gaidano , M Dal Bo , V Gattei , A Zucchetto

In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10-15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the very-late-activation-4 integrin, a well-known key regulator of microenviromental interactions, and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0.0001), occurring also outside the trisomy 12 CLL subset. Using both the MEC-1 CLL-like cells stably transfected with the NOTCH1 intracellular domain and primary CLL cells bearing a mutated or wild-type NOTCH1 gene configuration, we provide evidence that triggering of the NOTCH1 pathway resulted in a positive CD49d expression regulation, which was driven by a NOTCH1-dependent activation of nuclear factot-κB (NF-κB). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κB pathways resulted in impaired NF-κB nuclear translocation with consequent down-modulation of CD49d expression. Altogether, our data link for the first time NOTCH1 mutations to CD49d expression regulation through the involvement of the NF-κB pathway in CLL.

中文翻译:

在慢性淋巴细胞性白血病中,NOTCH1突变与高CD49d表达相关:NOTCH1与NF-κB通路之间的联系。

在慢性淋巴细胞性白血病(CLL)中,NOTCH1的稳定突变(影响多达10-15%的病例)与不良预后,疾病进展和化疗的难治性有关。NOTCH1突变在三体性12 CLL(一种经常表达CD49d的疾病亚群,非常晚期激活4整合素的α4链,微环境相互作用的著名关键调节子和CLL的阴性预后因子)中过分表达。在本研究中,通过分析广泛的1180 CLL队列,我们​​观察到NOTCH1突变的存在与CD49d(P <0.0001)的表达之间存在很强的关联,也发生在三体12 CLL子集之外。使用用NOTCH1细胞内结构域稳定转染的MEC-1 CLL样细胞和带有突变或野生型NOTCH1基因构型的原代CLL细胞,我们提供的证据表明NOTCH1途径的触发导致了CD49d表达的正调控,从而由NOTCH1依赖性核因子-κB(NF-κB)激活驱动。一致地,NOTCH1和/或NF-κB途径的药理学抑制作用导致NF-κB核易位受损,从而导致CD49d表达下调。总之,我们的数据首次通过将NF-κB通路参与CLL而将NOTCH1突变与CD49d表达调控联系起来。这是由核因子-κB(NF-κB)的NOTCH1依赖性激活驱动的。一致地,NOTCH1和/或NF-κB途径的药理学抑制作用导致NF-κB核易位受损,从而导致CD49d表达下调。总之,我们的数据首次通过将NF-κB通路参与CLL而将NOTCH1突变与CD49d表达调控联系起来。这是由核因子-κB(NF-κB)的NOTCH1依赖性激活驱动的。一致地,NOTCH1和/或NF-κB途径的药理学抑制作用导致NF-κB核易位受损,从而导致CD49d表达下调。总之,我们的数据首次通过将NF-κB通路参与CLL而将NOTCH1突变与CD49d表达调控联系起来。
更新日期:2017-09-22
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