The Role of the IRF4-NOTCH2 Interplay in B-Cell Development and Malignancy

IRF4-NOTCH2 相互作用在 B 细胞发育和恶性肿瘤中的作用

• 批准号: 268806633
• 负责人: Dr. Maja Milanovic
• 金额: --
• 依托单位: Department of Pathology and Cell Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268806633?language=en
• 关键词: Role; IRF4; NOTCH2; Interplay; Cell

The development of B lymphocytes is tightly controlled by the coordinated expression of master transcriptional regulators. Aberrant expression of these regulators due to genetic alterations can disrupt ordered B-cell development and contribute to oncogenic transformation. The transcription factor interferon regulatory factor-4 (IRF4) has been identified as a potential tumor suppressor in B-cell chronic lymphocytic leukemia (CLL), a malignancy of quiescent mature B cells. Towards understanding the function of IRF4 in B cells, the host laboratory has recently obtained evidence that IRF4 controls the migration and homing properties of mature B cells within the lymphoid tissues. Thus, it has been observed that the inducible deletion of the irf4 gene in vivo led to an accumulation of IRF4-deficient B cells in the lymphoid microenvironment of the marginal zone. Notably, NOTCH2 signaling was found to be hyperactivated in IRF4-deficient B cells, and inhibition of NOTCH2 signaling by a therapeutic monoclonal antibody led to a rapid disintegration of the marginal zone. These results are likely to be relevant for CLL, since published evidence suggests that NOTCH2 is constitutively active in CLL tumor cells. The underlying hypothesis is that alterations in the balance of the transcriptional network established by IRF4 and NOTCH2 may disrupt the normal migration and homing properties of B cells and thereby contribute to lymphomagenesis by aberrantly positioning transformed B cells in a lymphoid microenvironment that supports survival.Here I propose to elucidate the molecular mechanism by which IRF4 regulates NOTCH2 activation in B cells. In addition, I will determine the biological program controlled by NOTCH2 in IRF4-deficient B cells by performing a genome-wide identification of transcriptional targets. Finally, I will investigate the effects of a NOTCH2-inhibitory antibody on CLL cell phenotype and function in in vitro assays that mimic the CLL proliferation center microenvironment. Elucidating the functional interplay between IRF4 and NOTCH2 in normal B-cell physiology and its disruption in malignancy has the potential to provide the basis for developing innovative therapeutic strategies targeted at CLL and splenic marginal zone B-cell lymphoma, where NOTCH2 hyperactivation has been associated with tumor-promoting roles.

B淋巴细胞的发育受到主转录调节因子的协调表达的严格控制。由于遗传改变导致的这些调节因子的异常表达可破坏有序的B细胞发育并促成致癌转化。转录因子干扰素调节因子-4（IRF 4）已被鉴定为B细胞慢性淋巴细胞白血病（CLL）（一种静止成熟B细胞的恶性肿瘤）的潜在肿瘤抑制因子。为了理解IRF 4在B细胞中的功能，宿主实验室最近获得了IRF 4控制淋巴组织内成熟B细胞的迁移和归巢特性的证据。因此，已经观察到，体内irf 4基因的可诱导缺失导致IRF 4缺陷型B细胞在边缘区的淋巴微环境中积累。值得注意的是，发现NOTCH 2信号在IRF 4缺陷型B细胞中过度活化，并且治疗性单克隆抗体对NOTCH 2信号的抑制导致边缘区的快速崩解。这些结果可能与CLL相关，因为已发表的证据表明NOTCH 2在CLL肿瘤细胞中具有组成性活性。潜在的假设是，在由IRF 4和NOTCH 2建立的转录网络的平衡的改变可能会破坏正常的迁移和归巢特性的B细胞，从而有助于淋巴瘤的异常定位转化的B细胞在淋巴微环境中，支持survival. In这里，我建议阐明的分子机制，IRF 4调节NOTCH 2激活B细胞。此外，我将通过对转录靶点进行全基因组鉴定来确定IRF 4缺陷型B细胞中由NOTCH 2控制的生物程序。最后，我将研究NOTCH 2抑制性抗体对CLL细胞表型和功能的影响，在体外试验中模拟CLL增殖中心的微环境。阐明IRF 4和NOTCH 2在正常B细胞生理学中的功能相互作用及其在恶性肿瘤中的破坏有可能为开发针对CLL和脾边缘区B细胞淋巴瘤的创新治疗策略提供基础，其中NOTCH 2超活化与肿瘤促进作用相关。