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.
项目摘要
作为肿瘤发生的起始遗传事件,肿瘤易感基因的生殖系变异干扰细胞,
生长和分化并为恶性转化奠定基础。因此,癌症的研究
易感基因及其相关的遗传综合征提供了对正常生理学的重要见解
和癌症生物学。通过对常染色体显性遗传的血小板减少症和B-
急性淋巴细胞白血病(B-ALL),我们和其他人确定了影响ETV 6的致病性生殖系变异,
编码ETS变体6转录阻遏物的基因。随后,我们对生殖细胞样本进行了测序,
从4,405名B-ALL儿童中,在0.5%的患者中检测到类似的变异。进一步的关联研究
结果显示,在该ALL队列中,致病性ETV 6变异体显著富集22.94倍,而在134,187
gnomAD中的非ALL对照(P= 2.2 × 10-16)。这些数据坚定地支持我们的总体前提,即致病性
胚系ETV 6变异体易患儿童ALL。为了更好地了解胚系ETV 6变异体
促进白血病发生,我们使用体外试验来询问它们对编码的
ETV 6蛋白。值得注意的是,检测的每种致病性ETV 6变体都显著降低了ETV 6转录
阻遏物活性、ETV 6 DNA结合能力受损和ETV 6错误定位于细胞质。同时,我们
产生了一种新的小鼠模型,其携带复发性B-ALL相关Etv 6变体(Etv 6 R355 X)。初步
对Etv 6 R355 X/+小鼠的研究揭示了早期B细胞发育以及造血系统发育的显著扰动。
干细胞和祖细胞(HSPC)数量和功能。最后,我们获得了同基因诱导多能干细胞,
细胞(iPSC)系,其含有致病性ETV 6变体,其产生发育不良的巨核细胞,类似于
ETV 6变异阳性患者。基于这些结果,我们假设ETV 6变异体易患
所有这些都是通过扰乱损害造血发育的关键转录程序来实现的。在这项提案中,
我们将利用我们独特的模型系统来严格验证这一假设。在目标1中,我们将描述
携带或不携带致病性种系ETV 6的人类和小鼠的造血区室
变体。我们将检查WT和ETV 6变体阳性的iPSC或小鼠造血祖细胞是否能够在体外培养。
正确区分沿着不同的谱系。确定胚系ETV 6变异体如何影响基因表达
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
在小鼠和iPSC衍生的B祖细胞中鉴定推定的ETV 6靶基因
和携带WT或变体ETV 6的HSPC。最后,在目标3中,我们将进行全面的全基因组和
对B-ALL样本进行RNA测序,以阐明与生殖系一致的体细胞遗传病变
ETV 6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-
促进这些第二次打击的效果。该项目将为生殖细胞的影响提供新的见解,
遗传变异对造血和B-ALL(最常见的儿童癌症)的发展的影响。
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:
$ 20万 - 项目类别:
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
- 批准号:
8907502 - 财政年份:2014
- 资助金额:
$ 20万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
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8110525 - 财政年份:2007
- 资助金额:
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Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7662291 - 财政年份:2007
- 资助金额:
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Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
SAP、SLAM 和 Fyn 在 NKT 细胞个体发育和激活中的作用
- 批准号:
7302925 - 财政年份:2007
- 资助金额:
$ 20万 - 项目类别:
Role of SAP,SLAM and Fyn in NKT Cell Ontogeny and Activation
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- 批准号:
7886595 - 财政年份:2007
- 资助金额:
$ 20万 - 项目类别:
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7473119 - 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
SH2D1A/SAP 在 NKT 细胞发育和功能中的作用
- 批准号:
6852322 - 财政年份:2004
- 资助金额:
$ 20万 - 项目类别:
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