Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion
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NF-κB 和 Notch 信号传导的共激活足以诱导 B 细胞转化并实现 B 髓细胞转化
DOI：
10.1182/blood.2019001438
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发表时间：
2020-01-09
期刊：
影响因子：
20.3
通讯作者：
Zhao, Chen
中科院分区：
文献类型：
--
作者：
Xiu, Yan;Dong, Qianze;Zhao, Chen
NF-kappa B和Notch信号可以在多种B细胞淋巴瘤中同时激活。b细胞淋巴瘤患者偶尔会发生与克隆相关的髓系肿瘤，预后较差。这两种途径的同时激活是否足以诱导b细胞转化，以及该信号是否在病理背景下启动b - mybid转化，在很大程度上是未知的。在这里，我们提供了遗传证据，证明在B细胞中NF-kappa B和Notch信号的同时激活足以诱导B细胞淋巴瘤转化，并启动共同祖细胞通过去分化而不是转分化转化为髓系。有趣的是，转化的骨髓细胞可以进一步转化为骨髓性白血病，尽管频率很低。从机制上讲，nf - κ B和Notch信号的共同激活赋予了B细胞自我更新的能力。BACH2（淋巴瘤和髓细胞基因抑制因子）的下调，而CEBP/ α的上调和/或b细胞转录因子的下调，是b细胞转化和髓细胞转化的早期事件。有趣的是，一种DNA低甲基化药物不仅有效地消除了转化的髓系白血病细胞，而且恢复了在转化的髓系白血病细胞中丢失的绿色荧光蛋白的表达。综上所述，我们的研究结果表明，靶向NF-kappa B和Notch信号不仅可以改善淋巴瘤的治疗，还可以防止淋巴瘤向髓系肿瘤的转化。重要的是，DNA低甲基化药物可能有效治疗这些转化髓系肿瘤。
NF-kappa B and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myebid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-kappa B and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-kappa B and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBP/alpha and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-kappa B and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphomato-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.