Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia
ETV6相关急性淋巴细胞白血病的发病机制
基本信息
- 批准号:10247963
- 负责人:
- 金额:$ 20万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAffectB cell differentiationB-Cell Acute Lymphoblastic LeukemiaB-Cell DevelopmentB-LymphocytesBindingBiological AssayBiological ModelsBiologyBlood CellsCancer BiologyCancer EtiologyCancer-Predisposing GeneCell CountCell LineCell physiologyCellsChIP-seqChildChildhoodChildhood Acute Lymphocytic LeukemiaChromatinClinicalCollaborationsCytoplasmDNA BindingDataDatabasesDefectDevelopmentDifferentiation and GrowthDysplastic MegakaryocyteETV6 geneEpigenetic ProcessEventExhibitsFamilyGene ExpressionGenesGeneticGenetic TranscriptionGenetic VariationHematopoiesisHematopoieticHematopoietic stem cellsHeterozygoteHumanImpairmentIn VitroIndividualInheritedLesionLiteratureMalignant - descriptorMalignant Childhood NeoplasmMalignant NeoplasmsModelingMusMutant Strains MiceMutatePathogenesisPathogenicityPathway interactionsPatientsPhenotypePhysiciansPhysiologyPopulationPositioning AttributePredispositionProteinsPublic HealthRecurrenceReportingSaint Jude Children&aposs Research HospitalSamplingScientistSomatic MutationSyndromeTestingThrombocytopeniaTimeTranscription RepressorVariantXCL1 geneYangbasecell growthcellular developmentchildhood cancer mortalitycohortdisease classificationgenome sequencingimprovedin vitro Assayin vivoinduced pluripotent stem cellinsightleukemialeukemogenesismouse modelnovelpersonalized managementpreventprogenitorprognosticprogramsstem cellstranscription factortranscriptometranscriptome sequencingtransmission processtreatment optimizationtumorigenesiswhole genome
项目摘要
PROJECT SUMMARY
As the initiating genetic events in tumorigenesis, germline variants in cancer predisposing genes perturb cell
growth and differentiation and set the stage for malignant transformation. Accordingly, the study of cancer
predisposing genes and their associated hereditary syndromes provides critical insights into normal physiology
and cancer biology. By investigating families with autosomal dominant transmission of thrombocytopenia and B-
acute lymphoblastic leukemia (B-ALL), we and others identified pathogenic germline variants affecting ETV6,
the gene encoding the ETS variant 6 transcriptional repressor. Subsequently, we sequenced germline samples
from 4,405 children with B-ALL and detected similar variants in 0.5% of patients. Further association studies
revealed a significant 22.94-fold enrichment of pathogenic ETV6 variants in this ALL cohort compared to 134,187
non-ALL controls in gnomAD (P= 2.2 × 10-16). These data firmly support our overall premise that pathogenic
germline ETV6 variants predispose to childhood ALL. To better understand how germline ETV6 variants
promote leukemogenesis, we used in vitro assays to interrogate their effects on the functions of the encoded
ETV6 protein. Notably, each of the pathogenic ETV6 variants examined significantly reduced ETV6 transcription
repressor activity, impaired ETV6 DNA binding capacity and mis-localized ETV6 to the cytoplasm. In parallel, we
generated a novel mouse model harboring a recurrent B-ALL-associated Etv6 variant (Etv6R355X). Preliminary
studies of Etv6R355X/+ mice reveal significant perturbations in early B cell development, as well as hematopoietic
stem and progenitor cell (HSPC) number and function. Finally, we generated isogenic induced pluripotent stem
cell (iPSC) lines harboring pathogenic ETV6 variants, which generate dysplastic megakaryocytes, similar to
ETV6 variant positive patients. Based on these results, we hypothesize that ETV6 variants predispose to
ALL by perturbing key transcriptional programs that impair hematopoietic development. In this proposal,
we will make use of our unique model systems to rigorously test this hypothesis. In Aim 1, we will characterize
the hematopoietic compartments of humans and mice that do or do not harbor pathogenic germline ETV6
variants. We will examine whether WT and ETV6 variant-positive iPSCs or mouse hematopoietic progenitors
properly differentiate along various lineages. To establish how germline ETV6 variants influence gene expression
in developing hematopoietic progenitors, in Aim 2 we will use RNA-sequencing and ATAC-sequencing to explore
transcriptional landscapes and identify putative ETV6 target genes in mouse and iPSC-derived B progenitors
and HSPC harboring WT or variant ETV6. Finally, in Aim 3 we will perform comprehensive whole genome and
RNA-sequencing of B-ALL samples to elucidate the somatic genetic lesions that function in concert with germline
ETV6 variants to drive B-leukemogenesis. We will use in vitro and in vivo approaches to assess the leukemia-
promoting effects of these second hits. This project will provide new insights into the influence of germline
genetic variation on hematopoiesis and development of B-ALL, the most common childhood cancer.
项目概要
作为肿瘤发生的起始遗传事件,癌症易感基因的种系变异扰乱细胞
生长和分化,并为恶性转化奠定基础。据此,癌症研究
诱发基因及其相关的遗传综合征为正常生理学提供了重要的见解
和癌症生物学。通过调查血小板减少症和 B- 常染色体显性遗传家族
急性淋巴细胞白血病 (B-ALL),我们和其他人确定了影响 ETV6 的致病性种系变异,
编码 ETS 变体 6 转录抑制子的基因。随后,我们对种系样本进行了测序
研究人员对 4,405 名 B-ALL 儿童进行了研究,并在 0.5% 的患者中检测到了类似的变异。进一步的关联研究
与 134,187 例相比,该 ALL 队列中致病性 ETV6 变异显着富集 22.94 倍
gnomAD 中的非 ALL 对照 (P= 2.2 × 10-16)。这些数据有力地支持了我们的总体前提,即致病性
种系 ETV6 变异易患儿童 ALL。为了更好地了解种系 ETV6 变体如何
促进白血病发生,我们使用体外测定来探究它们对编码功能的影响
ETV6 蛋白。值得注意的是,每个致病性 ETV6 变异都显着降低了 ETV6 转录
抑制活性、ETV6 DNA 结合能力受损以及 ETV6 错误定位到细胞质。与此同时,我们
生成了一种新的小鼠模型,该模型含有复发性 B-ALL 相关 Etv6 变体 (Etv6R355X)。初步的
对 Etv6R355X/+ 小鼠的研究揭示了早期 B 细胞发育以及造血功能的显着扰动
干细胞和祖细胞 (HSPC) 的数量和功能。最后,我们生成了同基因诱导多能干
含有致病性 ETV6 变异的细胞 (iPSC) 系,可产生发育不良的巨核细胞,类似于
ETV6变异阳性患者。基于这些结果,我们假设 ETV6 变体倾向于
ALL 通过扰乱损害造血发育的关键转录程序而产生。在这个提案中,
我们将利用我们独特的模型系统来严格检验这一假设。在目标 1 中,我们将描述
人类和小鼠的造血区室含有或不含有致病性种系 ETV6
变种。我们将检查 WT 和 ETV6 变异阳性 iPSC 或小鼠造血祖细胞是否
正确区分不同的谱系。确定种系 ETV6 变异如何影响基因表达
在开发造血祖细胞方面,在目标 2 中,我们将使用 RNA 测序和 ATAC 测序来探索
转录景观并鉴定小鼠和 iPSC 衍生的 B 祖细胞中推定的 ETV6 靶基因
以及携带 WT 或变体 ETV6 的 HSPC。最后,在目标 3 中,我们将进行全面的全基因组和
B-ALL 样本的 RNA 测序可阐明与种系协同作用的体细胞遗传损伤
ETV6 变体驱动 B 白血病发生。我们将使用体外和体内方法来评估白血病-
这些第二次点击的促进效果。该项目将为生殖细胞系的影响提供新的见解
B-ALL(最常见的儿童癌症)的造血和发育的遗传变异。
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)
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KIM Erika NICHOLS其他文献
KIM Erika NICHOLS的其他文献
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{{ truncateString('KIM Erika NICHOLS', 18)}}的其他基金
Targeting the immunoproteasome as a novel therapeutic strategy for hemophagocytic lymphohistiocytosis
靶向免疫蛋白酶体作为噬血细胞性淋巴组织细胞增多症的新型治疗策略
- 批准号:
10741624 - 财政年份:2023
- 资助金额:
$ 20万 - 项目类别:
Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia
ETV6相关急性淋巴细胞白血病的发病机制
- 批准号:
10837399 - 财政年份:2020
- 资助金额:
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JAK inhibition as a novel treatment for hemophagocytic lymphohistiocytosis
JAK 抑制作为噬血细胞性淋巴组织细胞增多症的新型治疗方法
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8907502 - 财政年份:2014
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8110525 - 财政年份:2007
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Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
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- 批准号:
7662291 - 财政年份:2007
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Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
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7302925 - 财政年份:2007
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7886595 - 财政年份:2007
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6987827 - 财政年份:2004
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ROLE OF SH2D1A/SAP IN NKT CELL DEVELOPMENT AND FUNCTION
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6852322 - 财政年份:2004
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