The pathogenesis of chromosome 7q deletions in juvenile myelomonocytic leukemia
幼年型粒单核细胞白血病7q染色体缺失的发病机制
基本信息
- 批准号:9789218
- 负责人:
- 金额:$ 35.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-20 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdolescentAnemiaAutomobile DrivingBindingBloodBlood CellsCRISPR/Cas technologyCancer SurvivorCell SurvivalChildChildhoodChildhood Acute Myeloid LeukemiaChromosome ArmChromosome abnormalityChromosomesChromosomes, Human, Pair 7ComplementDataDevelopmentDiseaseDysmyelopoietic SyndromesDysplasiaEZH2 geneEngineeringEpigenetic ProcessEtiologyFutureGene DeletionGenesGeneticGenetic EpistasisGenetic ModelsGoalsGrowthHematopoieticIn VitroInfiltrationInheritedJuvenile Myelomonocytic LeukemiaLaboratoriesMalignant Childhood NeoplasmMalignant NeoplasmsModelingMolecularMusMutateMutationMyelodysplastic/Myeloproliferative DiseaseMyelogenousMyeloproliferative diseaseNeoplasmsOncogenicOther GeneticsOutcomePathogenesisPathway interactionsPatientsPenetrancePharmaceutical PreparationsPhysiologicalPredispositionRadiationRecurrenceReportingResearch PersonnelRoleSignal TransductionSiteStem cellsSyndromeTestingTranscriptional RegulationTumor Suppressor GenesWorkcell growthchemotherapychildhood cancer survivorchromosome 7 losschromosome 7q losscombinatorialdesigndosageearly childhoodgenome editinghigh riskhistone methyltransferasehomeodomainhuman diseaseimproved outcomein vivoknock-downleukemialeukemogenesismolecular targeted therapiesmouse modelnew therapeutic targetnovel therapeuticsoutcome forecastpre-clinicalprogramsscreeningself-renewalside effecttherapeutic targettherapy resistanttranscription factortreatment responsetumortumorigenesis
项目摘要
Pediatric malignancies frequently harbor chromosome-arm level copy number changes that potentially impact
the expression level of a large number of genes, yet how segmental alterations contribute to tumorigenesis
remains poorly defined. This is a major gap in our understanding of the pathogenesis of childhood cancers
and hampers the rational design of new therapies. One such deletion is loss of part or all of chromosome 7
[-7/del(7q)], the most common cytogenetic abnormality in myeloid malignancies of childhood. -7/del(7q) occurs
in up to 33% of juvenile myelomonocytic leukemias (JMML), which are aggressive myelodysplastic
syndrome/myeloproliferative neoplasms (MDS/MPN) characterized by RAS pathway mutations and few other
somatic alterations. In myeloid malignancies, -7/del(7q) is associated with treatment resistance and a poor
prognosis for reasons that are not understood. The long-term goal of this proposal is to understand the
molecular pathogenesis of -7/del(7q) and to reveal new therapeutic targets for JMML patients. In previous
work, we reported that the transcription factor, CUX1, is a highly conserved myeloid tumor suppressor gene
encoded on 7q. We demonstrated a striking association of oncogenic RAS pathway mutations with CUX1
deletions across tumor types. We recently engineered a Cux1 knockdown mouse model (Cux1low), which
develops a spontaneous MDS/MPN with features of human JMML, including myelomonocytic expansion in all
hematopoietic compartments with infiltration into non-hematopoietic tissues, dysplasia in all myeloid lineages,
and anemia. In addition to CUX1, 7q deletions are typically large and span other established or putative tumor
suppressor genes and/or myeloid regulators. In this proposal, we will test the hypothesis that 7q is a
`Contiguous gene syndrome' region, wherein combined dosage imbalance of multiple genes drives JMML, in
combination with oncogenic RAS signaling. We will use our unique mouse model and CRISPR/Cas9 genome
editing to achieve the following Specific Aims: 1) Identify the cellular and molecular mechanisms by which
Cux1 knockdown and Ras cooperate in JMML; 2) Define the pathogenesis of combinatorial dosage imbalance
of 7q genes in JMML. This work will have a positive impact on the field of myeloid malignancies by: i)
elucidating the molecular mechanisms by which combinatorial loss of 7q genes drives disease; ii) identifying
new molecular targets for the treatment of JMML; and iii) establishing a physiologically accurate mouse model
in which novel therapies for human disease can be rapidly tested and optimized. Our mouse model of JMML
will fulfill a major unmet need for childhood myeloid malignancies, specifically a preclinical mouse model for
screening of approved and experimental drugs in future studies. Our work will reveal the relevant proliferative
and differentiation pathways for therapeutic targets to test in this model.
儿童恶性肿瘤经常存在染色体臂水平的拷贝数变化,这可能会影响
大量基因的表达水平,但节段性改变如何促进肿瘤的发生
仍然没有明确的定义。这是我们对儿童癌症发病机制认识上的一大空白。
并阻碍了新疗法的合理设计。一种这样的缺失是丢失部分或全部7号染色体
[-7/del(7q)],是儿童髓系恶性肿瘤最常见的细胞遗传学异常。-7/del(7q)发生
高达33%的青少年粒单核细胞白血病(JMML)是侵袭性骨髓增生异常
以RAS途径突变为特征的综合征/骨髓增生性肿瘤(MDS/MPN)
躯体的变化。在髓系恶性肿瘤中,-7/del(7q)与治疗耐药和不良反应有关
预后的原因尚不清楚。这项建议的长期目标是理解
-7/del(7q)的分子发病机制,并为JMML患者提供新的治疗靶点。在以前的
工作中,我们报道了转录因子CUX1是一种高度保守的髓系肿瘤抑制基因
编码在7q上。我们发现致癌RAS途径突变与CUX1显著相关
所有肿瘤类型的缺失。我们最近设计了一个CUX1基因敲除小鼠模型(Cux1low),它
发展出一种具有人类JMML特征的自发MDS/MPN,包括ALL中的骨髓单核细胞扩张
向非造血组织渗透的造血室,所有髓系不典型增生,
还有贫血。除CUX1外,7q缺失通常较大,并横跨其他已确诊或可能的肿瘤
抑制基因和/或髓系调节剂。在这个提案中,我们将测试7q是一个
‘连续基因综合征’区,其中多个基因的联合剂量失衡驱动JMML,在
与致癌RAS信号相结合。我们将使用我们独特的小鼠模型和CRISPR/Cas9基因组
编辑以实现以下特定目标:1)确定细胞和分子机制
CUX1基因下调和RAS在JMML中的协同作用;2)明确了组合剂量失衡的发病机制
7q基因在JMML中的分布。这项工作将对髓系恶性肿瘤领域产生积极影响:i)
阐明7q基因组合缺失导致疾病的分子机制;ii)鉴定
治疗JMML的新分子靶点;以及iii)建立生理上准确的小鼠模型
其中人类疾病的新疗法可以被快速测试和优化。我们的JMML小鼠模型
将满足儿童髓系恶性肿瘤的主要未得到满足的需求,特别是临床前小鼠模型
在未来的研究中对批准的和实验的药物进行筛选。我们的工作将揭示相关的增殖剂
以及治疗靶点的分化途径在这个模型中进行测试。
项目成果
期刊论文数量(0)
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Megan McNerney其他文献
Megan McNerney的其他文献
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{{ truncateString('Megan McNerney', 18)}}的其他基金
Establishing CUX1 as a determinant of hematopoietic stem cell fate
确定 CUX1 作为造血干细胞命运的决定因素
- 批准号:
10558905 - 财政年份:2022
- 资助金额:
$ 35.42万 - 项目类别:
The pathogenesis of chromosome 7q deletions in juvenile myelomonocytic leukemia
幼年型粒单核细胞白血病7q染色体缺失的发病机制
- 批准号:
10229402 - 财政年份:2018
- 资助金额:
$ 35.42万 - 项目类别:
The pathogenesis of chromosome 7q deletions in juvenile myelomonocytic leukemia
幼年型粒单核细胞白血病7q染色体缺失的发病机制
- 批准号:
10471201 - 财政年份:2018
- 资助金额:
$ 35.42万 - 项目类别:
Determining the role of CUX1 in myeloid neoplasia
确定 CUX1 在骨髓瘤形成中的作用
- 批准号:
8820577 - 财政年份:2014
- 资助金额:
$ 35.42万 - 项目类别:
Next-Generation Sequencing of Therapy-Related Acute Myeloid Leukemia
治疗相关急性髓系白血病的下一代测序
- 批准号:
7915136 - 财政年份:2010
- 资助金额:
$ 35.42万 - 项目类别:
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