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

NF-kB 和 Notch 信号在 B 细胞淋巴瘤转化和 B 细胞可塑性中的协同作用

• 批准号: 10383699
• 负责人: Chen Zhao
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383699
• 关键词: Apoptosis; B Cell Proliferation; B-Cell Activation; B-Cell Development; B-Cell Lymphomas; B-Lymphocytes; BACH2 gene; CCAAT-Enhancer-Binding Protein-alpha; CD19 gene; Cellular biology; Clinical; Clonality; Clone Cells; Data; Development; Diagnosis; Diagnostic; Disease; Down-Regulation; Enhancers; Environment; Event; Exposure to; Health; Herbicides; Hodgkin Disease; Human; Immunoglobulins; Lymphoma; Malignant - descriptor; Mature B-Lymphocyte; Myelogenous; Myeloid Cells; Myeloid Leukemia; Myeloproliferative disease; NF-kappa B; Non-Hodgkin' s Lymphoma; Pathologic; Pathway interactions; Patients; Prognosis; Regimen; Research; Risk; Role; Signal Pathway; Signal Transduction; Somatic Mutation; Spleen; Testing; Therapeutic; Transplantation; Up-Regulation; V(D)J Recombination; Veterans; advanced disease; agent orange; cell transformation; cytokine; experience; improved; inhibitor; leukemic transformation; military service; notch protein; overexpression; premalignant; prevent; standard care; stemness; synergism; transcription factor; transdifferentiation

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.

NF-kB和Notch信号在几乎所有常见的B细胞淋巴瘤中被激活，这是由于激活 体细胞突变或途径调节物的上调。然而，这两种途径如何协同作用 调节B细胞发育和淋巴瘤转化尚不清楚。B细胞的可塑性已经被 几十年前在临床上就被发现了。B细胞淋巴瘤患者偶尔会发生克隆性相关髓样 这表明至少一些髓系肿瘤是由恶性或癌前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，由于诊断性疾病而预后不良。 困难和缺乏标准治疗。问题是，B细胞如何转化为髓系细胞？ 在实验中，在成熟B细胞中强制表达髓样转录因子CEBPa诱导B-髓样 转换.然而，CEBPa是否在病理条件下启动B-髓样转化以及是否 其他信号通路也涉及很大程度上是未知的。我们的初步数据显示， CD 19 + B细胞中两种途径的激活有效诱导急剧的B细胞淋巴瘤转化 与单独激活任一途径相反。有趣的是，出乎意料的是，移植的双重激活 边缘区前体B细胞，但不是边缘区B细胞，通过 去分化，和一些转化为髓性白血病与克隆免疫球蛋白VDJ重组。 我们的中心假设是NF-kB和Notch信号的同时激活加速了B细胞 Bach 2的表达下调，Bach 2的表达上调，Bach 2的表达 Ezh 2.我们将用以下两个独立的具体目标来检验这一假设：1）确定 NF-κ B/Notch信号传导的同时激活诱导B细胞转化的机制，和2） 确定NF-kB/Notch信号传导的同时激活诱导B-髓样 转换和转化。预期结果与理解协同作用高度相关 NF-κ B/Notch信号在B细胞可塑性和恶性转化中的作用重要的是，我们的研究结果表明， 在目前的淋巴瘤治疗方案中加入Notch、NF-kB和/或Ezh 2抑制剂不仅可以 改善淋巴瘤治疗，而且还防止髓样肿瘤转化。

项目成果

TIFAB accelerates MLL-AF9-Induced acute myeloid leukemia through upregulation of HOXA9.

• DOI: 10.1016/j.isci.2021.103425
• 发表时间: 2021-12-17
• 期刊: iScience
• 影响因子: 5.8
• 作者: Zhao J;Xiu Y;Fu L;Dong Q;Borcherding N;Wang Y;Li Q;De Silva NS;Klein U;Boyce BF;Zhao C
• 通讯作者: Zhao C