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: 10253632
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253632
• 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; Military Personnel; Myelogenous; Myeloid Cells; Myeloid Leukemia; Myeloproliferative disease; NF-kappa B; Non-Hodgkin' s Lymphoma; Pathologic; Pathway interactions; Patients; Regimen; Research; Risk; Role; Services; 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/antagonist; leukemic transformation; notch protein; outcome forecast; 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细胞淋巴瘤中都被激活