Synergy of NF-kB and Notch signaling in B cell lymphomatous transformation and B cell plasticity

核因子-kB和Notch信号在几乎所有常见的B细胞淋巴瘤中都被激活，这是因为 途径调节因子的体细胞突变或上调。然而，这两条途径是如何协同的 调控B细胞发育和淋巴瘤转化的机制尚不清楚。B细胞的可塑性一直是 几十年前临床上就已经认识到了。B细胞淋巴瘤患者偶尔发展为克隆性髓系 肿瘤，提示至少一些髓系肿瘤是从恶性或癌前B细胞发展而来的。 在临床上，这些患者通常表现为晚期疾病，由于确诊，预后较差。 困难和缺乏标准的治疗。问题是，B细胞是如何转变为髓系的？ 实验上，在成熟的B细胞中强制表达髓系转录因子CEBPA可诱导B髓系细胞 转换。然而，CEBPA是否在病理条件下启动B髓系转换，以及是否 其他信号通路也在很大程度上是未知的。我们的初步数据显示同时 CD19 B细胞中两条通路的激活可有效诱导急性髓细胞白血病的B细胞淋巴瘤转化 而不是单独激活这两条途径中的一条。有趣而出人意料的是，移植了双重激活的 边缘带前体B细胞，而不是边缘带B细胞，通过 去分化，部分以克隆性免疫球蛋白VDJ重组转化为髓系白血病。 我们的中心假设是同时激活核因子-kB和Notch信号可加速B细胞 转化和触发B-髓系转化主要通过下调Bach2和上调Bach2 EZH2.我们将通过以下两个独立的具体目标来检验这一假设：1)确定 同时激活NF-kB/Notch信号诱导B细胞转化的机制，以及2) 确定同时激活核因子-kB/Notch信号诱导B髓系细胞的机制 转换和转型。预期结果与理解协同作用高度相关 核转录因子-kB/Notch信号在B细胞可塑性和恶变中的作用重要的是，我们的结果表明 在目前的淋巴瘤治疗方案中加入Notch、NF-kB和/或Ezh2抑制剂不仅可以 提高淋巴瘤治疗水平的同时，也能防止髓系肿瘤转化。

NF-kB and Notch signaling are activated in almost all common B cell lymphomas due to either activating somatic mutations or upregulation of pathway regulators. However, how these two pathways synergistically regulate B cell development and lymphomatous transformation are unclear. B cell plasticity has been recognized clinically decades ago. Patient with B cell lymphoma occasionally develop clonally-related myeloid tumors, suggesting that at least some myeloid tumors develop from malignant or premalignant B cells. Clinically, these patients typically present with advanced disease with a poor prognosis due to diagnostic difficulties and lack of standard treatment. The question is, how do B cells convert to myeloid lineage? Experimentally, forced expression of myeloid transcription factor, CEBPa, in mature B cells induces B-myeloid conversion. However, whether CEBPa initiates B-myeloid conversion in pathological conditions and whether other signaling pathways are also involved are largely unknown. Our preliminary data show that concurrent activation of both pathways in CD19+ B cells efficiently induces B cell lymphomatous transformation in sharp contrast to activation of either pathway alone. Intriguingly and unexpectedly, transplanted doubly-activated marginal zone precursor B cells, but not marginal zone B cells, converted to myeloid cells through dedifferentiation, and some transformed to myeloid leukemia with clonal immunoglobulin VDJ recombination. Our central hypothesis is that concurrent activation of NF-kB and Notch signaling accelerates B cell transformation and triggers B-myeloid conversion mainly through downregulation of Bach2 and upregulation of Ezh2. We will test this hypothesis with the following two independent specific aims: 1) To determine the mechanism whereby concurrent activation of NF-kB/Notch signaling induces B cell transformation, and 2) To determine the mechanism whereby concurrent activation of NF-kB/Notch signaling induces B-myeloid conversion and transformation. The expected results are highly relevant to understanding the synergistic role of NF-kB/Notch signaling in B cell plasticity and malignant transformation. Importantly, our results suggest that adding Notch, NF-kB and/or Ezh2 inhibitors to the current lymphoma therapeutic regimens could not only improve lymphoma treatment, but also prevent myeloid neoplasm conversion.