Role of MLL2 Gene Inactivation in B cell Non Hodgkin Lymphoma
MLL2 基因失活在 B 细胞非霍奇金淋巴瘤中的作用
基本信息
- 批准号:8422377
- 负责人:
- 金额:$ 33.2万
- 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:2013-01-01 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAlgorithmsAllelesB-Cell DevelopmentB-Cell NonHodgkins LymphomaB-LymphocytesBCL2 geneBCL6 geneBindingBiochemicalBiologicalBiological AssayBiological ProcessC-terminalChIP-seqChromosomal translocationClinicalDeletion MutationDevelopmentDiagnosisDiagnosticDiseaseEpigenetic ProcessEvolutionFollicular LymphomaFrequenciesGene Expression ProfileGene MutationGene SilencingGenesGeneticGenomeGenomicsGoalsHistonesHumanHypermethylationImmunotherapyIndolentLesionLymphomaLymphomagenesisMLL2 geneMaintenanceMalignant NeoplasmsMature B-LymphocyteMessenger RNAMissense MutationModelingMolecularMouse StrainsMutant Strains MiceMutationNatureNon-Hodgkin&aposs LymphomaOncogenicOutcomePathogenesisPathologicPathway interactionsPatientsPatternPoint MutationPredispositionProteinsProto-OncogenesRecurrenceResearch PriorityResearch ProposalsRoleSingle Nucleotide PolymorphismStructure of germinal center of lymph nodeSubstrate InteractionSystems BiologyTechnologyTherapeuticTumor Suppressor Genesbasechromatin remodelingdensitydisorder preventiondosageenzyme substrateexomeexome sequencinggenome-wideimprovedin vivoinsightlarge cell Diffuse non-Hodgkin&aposs lymphomamouse modelnext generationnovel therapeutic interventionpre-clinicalprogramspromoterpublic health relevancetherapeutic targettooltranscriptome sequencingtumor
项目摘要
DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma (B- NHL), accounting for 30-40% of the de-novo diagnoses and also arising as a frequent clinical evolution of follicular lymphoma (FL). Despite remarkable advances in both diagnosis and treatment, DLBCL remains a significant clinical challenge, as nearly 50% of patients are not cured by available therapeutic approaches. Major efforts are needed toward the identification of the molecular mechanisms that are responsible for disease development and maintenance, and can be therapeutically targeted. Recent analysis by us (Pasqualucci et al., Nature 2011; Pasqualucci et al., Nature Genetics 2011) and others (Morin et al., Nature 2011) using genome-wide approaches including next generation whole-exome sequencing and high-density single nucleotide polymorphism array analysis have characterized the landscape of genomic lesions that are associated with DLBCL, and have led to the identification of recurrent structural alterations in multiple histone/chromati remodeling genes. Among the recently discovered genetic lesions, the MLL2 histone H3K4 trimethyltransferase emerged as the most common target. Overall, ~30% of DLBCL and 89% of FL patients display somatic point mutations that remove the C-terminal enzymatic domain of MLL2, leading to its inactivation (Pasqualucci et al., Nature Genetics 2011; Morin et al., Nature 2011). The extremely high frequency of these lesions and their clearly disruptive nature in DLBCL and FL, the two major subtypes of B- NHL (combined, up to 70% of all diagnoses) indicate a central role for MLL2 in the pathogenesis of these malignancies. Building on these results, the general goal of this project will be to elucidate the normal and pathologic function o MLL2 in B cells, with the following Specific Aims: i) characterize the full spectrum of genetic and
epigenetic mechanisms of inactivation affecting MLL2 and its paralogue MLL3 in DLBCL and FL; ii) identify the transcriptional network that is regulated by MLL2 in normal B cells, and is disrupted in DLBCL as a consequence of MLL2 inactivating mutations; iii) examine the role of MLL2 deficiency in lymphomagenesis in vivo, alone or in cooperation with two additional genetic lesions that are found recurrently associated with MLL2 mutations in the human tumors, namely chromosomal translocations of the proto-oncogenes BCL2 and BCL6. The results obtained from the proposed studies are expected to provide i) significant new information toward our understanding of the mechanistic factors that underlie the pathogenesis of these two common B- NHLs, ii) mouse models of MLL2-driven lymphomagenesis that may serve for preclinical therapeutic targeting; iii) insights into novel therapeutic approaches, thus paving the basis for further advancements in disease prevention and treatment.
描述(由申请人提供):弥漫性大B细胞淋巴瘤(DLBCL)代表了非霍奇金淋巴瘤(B-NHL)最常见的形式,占DE-NOVO诊断的30-40%,也是卵泡淋巴瘤(FL)的常见临床进化。尽管诊断和治疗方面都取得了显着进步,但DLBCL仍然是一个重大的临床挑战,因为将近50%的患者无法通过可用的治疗方法治愈。为了鉴定负责疾病发展和维持的分子机制,需要进行重大努力,并且可以针对治疗。 Recent analysis by us (Pasqualucci et al., Nature 2011; Pasqualucci et al., Nature Genetics 2011) and others (Morin et al., Nature 2011) using genome-wide approaches including next generation whole-exome sequencing and high-density single nucleotide polymorphism array analysis have characterized the landscape of genomic lesions that are associated with DLBCL, and have led to the identification of recurrent structural多种组蛋白/染色体重塑基因的改变。在最近发现的遗传病变中,MLL2组蛋白H3K4三甲基转移酶是最常见的靶标。总体而言,约有30%的DLBCL和89%的FL患者表现出体细胞突变,这些突变消除了MLL2的C末端酶促结构域,从而导致其失活(Pasqualucci等人,自然遗传学,2011; Morin等,自然,2011)。这些病变的极高频率及其在DLBCL和FL中的明显破坏性,B-NHL的两个主要亚型(合并,最多70%的所有诊断)表明MLL2在这些恶性肿瘤的发病机理中起着核心作用。 在这些结果的基础上,该项目的一般目标将是阐明B细胞中的正常和病理功能O MLL2,并具有以下特定目的:i)表征遗传和遗传范围
DLBCL和FL中影响MLL2及其旁产物MLL3的灭活的表观遗传机制; ii)确定在正常B细胞中由MLL2调节的转录网络,并在DLBCL中破坏了MLL2灭活突变; iii)检查单独的MLL2缺乏症在体内的淋巴作用中,或与其他两个与人类肿瘤中MLL2突变相关的其他遗传病变合作,即原始cogenes bcl2和bcl6的染色体易位。 预计从拟议的研究中获得的结果将提供i)为理解这两种常见B-NHL的发病机理的理解的重要新信息,ii)MLL2驱动的淋巴细胞造成的小鼠模型,这些模型可能用于临床前治疗靶向; iii)对新型治疗方法的见解,从而为疾病预防和治疗的进一步发展铺平了基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Laura Pasqualucci其他文献
Laura Pasqualucci的其他文献
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{{ truncateString('Laura Pasqualucci', 18)}}的其他基金
Role of CREBBP missense mutations in lymphomagenesis
CREBBP错义突变在淋巴瘤发生中的作用
- 批准号:
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- 资助金额:
$ 33.2万 - 项目类别:
Role of CREBBP missense mutations in lymphomagenesis
CREBBP错义突变在淋巴瘤发生中的作用
- 批准号:
10544332 - 财政年份:2022
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$ 33.2万 - 项目类别:
The coding genome of HIV-associated plasmablastic lymphomas in South Africa
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8841047 - 财政年份:2015
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$ 33.2万 - 项目类别:
Role of KMT2D Gene Inactivation in B cell Non Hodgkin Lymphoma
KMT2D 基因失活在 B 细胞非霍奇金淋巴瘤中的作用
- 批准号:
10198854 - 财政年份:2013
- 资助金额:
$ 33.2万 - 项目类别:
Role of KMT2D Gene Inactivation in B cell Non Hodgkin Lymphoma
KMT2D 基因失活在 B 细胞非霍奇金淋巴瘤中的作用
- 批准号:
10432012 - 财政年份:2013
- 资助金额:
$ 33.2万 - 项目类别:
Role of MLL2 Gene Inactivation in B cell Non Hodgkin Lymphoma
MLL2 基因失活在 B 细胞非霍奇金淋巴瘤中的作用
- 批准号:
8600247 - 财政年份:2013
- 资助金额:
$ 33.2万 - 项目类别:
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