IRF8 and lymphomagenesis
IRF8 和淋巴瘤发生
基本信息
- 批准号:9898227
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2021-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The advent of massive parallel sequencing highlighted the genetic complexity of cancer, and unveiled the
putative contribution of several unsuspected genes to the process of malignant transformation. These
advances also indicated a need for the systematic examination of newly-found mutant genes as to determine
whether they truly contribute to cancer pathogenesis, or simply represent innocuous variants irrelevant to the
observed phenotype. Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in
adults, is curable in only ~60% of cases. This clinical challenge is associated with the disease’s complex
genetics, which include disruption of epigenetic modifiers, constitutive activation of the NF-κB pathway, and
deregulation of B cell relevant transcription factors. The latter, can derive from chromosomal translocation,
genomic amplification/deletions and somatic mutations. Recently, we developed an IGH-targeted
capture/sequencing strategy and discovered novel aberrant gene fusions in DLBCL including the juxtaposing
of IRF8 (interferon regulatory factor 8) to the IGH locus, t(14;16)(q32;q24), a prototypical model of transcription
factor deregulation in B cell lymphomas. Independently, IRF8 was found to be somatically mutated in ~10% of
DLBCL biopsies. Interestingly, close to 50% of the IRF8-mutant DLBCLs also have mutations in KMT2D, a
histone methyltransferase that when inactivated enhances the lymphomagenic potential of other genetic
lesions. IRF8, a member of the interferon family of transcription factors, is expressed in the germinal center
(GC) where it directly influences the expression of several key regulators of the GC reaction, including BCL6,
AICDA and PRDM1. The central objective of this proposal is to test the hypothesis that IRF8 is a bona fide
oncogene in DLBCL, which can be deregulated by chromosomal translocation and somatic mutations. To
advance this concept, we found that ectopic expression of IRF8 in DLBCL cell lines promotes a
lymphomagenic profile characterized by induction of BCL6 and AICDA, suppression of PRDM1 and resistance
to apoptosis. In addition, we generated preliminary data to show that the missense IRF8 mutants found in
DLBCL are all gain-of-function. Lastly, we created a mouse with B cell restricted transgenic expression of Irf8.
Building on our preliminary data, and on the availability of this novel animal model, we propose to address the
following specific aims: 1) Determine the mechanism for Irf8 lymphomagenesis in a mouse model that mimics
the IGH/IRF8 fusion found in human DLBCL; 2) Characterize in vivo the pro-lymphoma cooperation between
the oncogenic Irf8 and the tumor suppressor Kmt2d; 3) Define the functional consequences of the somatic
IRF8 mutations found in DLBCL. When this project is completed, we will show that IRF8 functions as an
oncogene that cooperates with KMT2D loss for the development of DLBCL. We also expect to mechanistically
link IRF8’s lymphomagenesis to the deregulation of BCL6, AICDA and PRDM1.
大规模平行测序的冒险突出了癌症的遗传复杂性,并揭示了
几个无刺基因对恶性转化过程的推定贡献。这些
进步还表明,需要对新发现的突变基因进行系统检查以确定
它们是真正有助于癌症发病机理,还是只是代表与无关的无害变体
观察到的表型。扩散的大B细胞淋巴瘤(DLBCL),这是最常见的淋巴恶性肿瘤
成人,仅在约60%的病例中可以治愈。这种临床挑战与疾病的复合物有关
遗传学包括破坏表观遗传修饰剂,NF-κB途径的组成型激活和
放松B细胞相关转录因子的管制。后者可以源自染色体易位,
基因组扩增/缺失和体细胞突变。最近,我们开发了一个目标
捕获/测序策略,并在DLBCL中发现了新颖的异常基因融合,包括并列
IRF8(干扰素调节因子8)的IGH基因座,t(14; 16)(Q32; Q24),一种转录的原型模型
B细胞淋巴瘤中的因子失调。独立地,发现IRF8在〜10%的体外突变
DLBCL活检。有趣的是,接近50%的IRF8突变剂DLBCL在KMT2D中也有突变
Hisstone甲基转移酶当灭活时增强了其他遗传的淋巴细胞增长潜力
病变。 IRF8是干扰素转录因子家族的成员,在生发中心表示
(GC)直接影响GC反应的几个关键调节剂的表达,包括Bcl6,
AICDA和PRDM1。该提议的核心目的是检验IRF8是真正的假设
DLBCL中的癌基因可以通过染色体易位和体细胞突变来放松调节。到
提出了这个概念,我们发现DLBCL细胞系中IRF8的生态表达促进了
以诱导Bcl6和AICDA的抑制作用和抗性为特征
凋亡。此外,我们生成了初步数据,以表明在
DLBCL都是功能收益。最后,我们创建了一个用B细胞限制IRF8的转基因表达的小鼠。
以我们的初步数据为基础,并基于这种新型动物模型的可用性,我们建议解决
以下特定目的:1)在小鼠模型中确定IRF8淋巴作用的机制
在人DLBCL中发现的IGH/IRF8融合; 2)在体内表征
致癌IRF8和肿瘤抑制剂KMT2D; 3)定义躯体的功能后果
DLBCL中发现的IRF8突变。该项目完成后,我们将证明IRF8起作用
与KMT2D损失合作以开发DLBCL的癌基因。我们也期望机械
将IRF8的淋巴作用与BCL6,AICDA和PRDM1的放松管联系起来。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
Ricardo C Aguiar的其他基金
Mitochondrial 2-hydroxyglutarate dehydrogenases modulate the cellular epitranscriptome
线粒体 2-羟基戊二酸脱氢酶调节细胞表观转录组
- 批准号:1011757510117575
- 财政年份:2021
- 资助金额:----
- 项目类别:
Mitochondrial 2-hydroxyglutarate dehydrogenases modulate the cellular epitranscriptome
线粒体 2-羟基戊二酸脱氢酶调节细胞表观转录组
- 批准号:1032219410322194
- 财政年份:2021
- 资助金额:----
- 项目类别:
Mitochondrial 2-hydroxyglutarate dehydrogenases modulate the cellular epitranscriptome
线粒体 2-羟基戊二酸脱氢酶调节细胞表观转录组
- 批准号:1054123410541234
- 财政年份:2021
- 资助金额:----
- 项目类别:
Post-Translational Control of TET Function in Lymphoma
淋巴瘤 TET 功能的翻译后控制
- 批准号:1025148210251482
- 财政年份:2013
- 资助金额:----
- 项目类别:
Post-Translational Control of TET Function in Lymphoma
淋巴瘤 TET 功能的翻译后控制
- 批准号:1051205410512054
- 财政年份:2013
- 资助金额:----
- 项目类别:
Non-coding RNAs at the interface of aberrant NF-kB signals and lymphomagenesis
异常 NF-kB 信号与淋巴瘤发生界面的非编码 RNA
- 批准号:89742978974297
- 财政年份:2013
- 资助金额:----
- 项目类别:
Non-coding RNAs at the interface of aberrant NF-kB signals and lymphomagenesis
异常 NF-kB 信号与淋巴瘤发生界面的非编码 RNA
- 批准号:84367048436704
- 财政年份:2013
- 资助金额:----
- 项目类别:
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