CLL模型中TLR9激动剂的分子生物学效应

Haematologica

2017-08-03Article

7.702

影响因子

原标题:TLR9刺激可诱导慢性淋巴细胞白血病细胞中的IkappaBzeta表达和IgM分泌

① 慢性淋巴细胞白血病(CLL)细胞的存活依赖于外部刺激,抗原受体和共刺激受体都能调节白血病细胞的存活和增值;② TLR9配体CpG能诱导所有分析样品中的NFKBIZ mRNA,通过意想不到的转录后机制,在一组选择病例中诱导IkappaBzeta蛋白表达;③ IkappaBzeta在维持CpG诱导的细胞存活和化学耐药性中有因果作用,CpG刺激可通过IkappaBzeta-阳性恶性肿瘤细胞释放免疫球蛋白分泌;④ IkappaBzeta可作为CLL中不同关键通路的标志物和效应分子。

慢性淋巴细胞白血病(CLL) Toll样受体(TLR) 免疫球蛋白

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Title:
TLR9 stimulation can induce IkappaBzeta expression and IgM secretion in chronic lymphocytic leukemia cells

DOI:
10.3324/haematol.2017.165878

Abstract & Authors展开

Abstract:
Chronic lymphocytic leukemia cells strongly depend on external stimuli for their survival. Both antigen receptor and co-stimulatory receptors including Toll-Like Receptors can modulate viability and proliferation of leukemic cells. Toll-Like Receptors ligands, and particularly the TLR9 ligand CpG, mediate heterogeneous responses in patient samples reflecting their clinical course. However, the molecular framework of the key signaling events underlying such heterogeneity is undefined. We focused our studies on a subset of chronic lymphocytic leukemia cases characterized by expression of CD38 and unmutated immunoglobulin genes, that respond to CpG with enhanced metabolic cell activity. We report that, while CpG induces NFKBIZ mRNA in all the samples analyzed, it induces the IkappaBzeta protein in a selected group of cases, through an unanticipated post-transcriptional mechanism. Interestingly, IkappaBzeta plays a causal role in sustaining CpG-induced cell viability and chemoresistance, and CpG stimulation can unleash immunoglobulin secretion by IkappaBzeta-positive malignant cells. These results identify and characterize IkappaBzeta as a marker and effector molecule of distinct key pathways in chronic lymphocytic leukemia.

All Authors:
Eleonora Fonte,Maria Giovanna Vilia,Daniele Reverberi,Ilenia Sana,Lydia Scarfò,Pamela Ranghetti,Ugo Orfanelli,Simone Cenci,Giovanna Cutrona,Paolo Ghia,Marta Muzio

First Authors:
Eleonora Fonte

Correspondence:
Marta Muzio

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