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

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.
儿科恶性肿瘤经常存在染色体臂水平拷贝数变化,可能会影响 大量基因的表达水平,以及片段改变如何促进肿瘤发生 仍然不明确。这是我们对儿童癌症发病机制理解的一个重大差距 并阻碍新疗法的合理设计。其中一种缺失是 7 号染色体部分或全部丢失 [-7/del(7q)],儿童骨髓恶性肿瘤中最常见的细胞遗传学异常。 -7/del(7q) 发生 高达 33% 的幼年型粒单核细胞白血病 (JMML) 属于侵袭性骨髓增生异常 以 RAS 通路突变和少数其他突变为特征的综合征/骨髓增生性肿瘤 (MDS/MPN) 躯体改变。在骨髓恶性肿瘤中,-7/del(7q) 与治疗耐药性和较差的治疗效果相关。 预后的原因尚不清楚。该提案的长期目标是了解 -7/del(7q) 的分子发病机制并揭示 JMML 患者的新治疗靶点。在之前的 在这项工作中,我们报道了转录因子 CUX1 是一种高度保守的骨髓肿瘤抑制基因 编码在 7q 上。我们证明了致癌 RAS 通路突变与 CUX1 之间存在显着关联 跨肿瘤类型的缺失。我们最近设计了 Cux1 敲除小鼠模型 (Cux1low), 开发出具有人类 JMML 特征的自发 MDS/MPN,包括所有骨髓单核细胞的扩张 造血室浸润到非造血组织,所有骨髓谱系发育不良, 和贫血。除了 CUX1 之外,7q 缺失通常很大并且跨越其他已确定或假定的肿瘤 抑制基因和/或骨髓调节因子。在这个提案中,我们将测试 7q 是一个假设 “连续基因综合症”区域,其中多个基因的组合剂量不平衡驱动 JMML, 与致癌 RAS 信号传导相结合。我们将使用我们独特的小鼠模型和 CRISPR/Cas9 基因组 编辑以实现以下具体目标:1)确定细胞和分子机制 Cux1敲低和Ras在JMML中合作; 2) 定义组合剂量不平衡的发病机制 JMML 中的 7q 基因。这项工作将通过以下方式对骨髓恶性肿瘤领域产生积极影响:i) 阐明 7q 基因组合丢失导致疾病的分子机制; ii) 识别 治疗 JMML 的新分子靶点; iii) 建立生理学精确的小鼠模型 其中可以快速测试和优化人类疾病的新疗法。我们的 JMML 鼠标模型 将满足儿童骨髓恶性肿瘤的主要未满足需求,特别是临床前小鼠模型 在未来的研究中筛选已批准和实验药物。我们的工作将揭示相关的增殖 以及在此模型中测试的治疗靶标的分化途径。

项目成果

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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:
Regulation of hematopoiesis by CUX1
CUX1 对造血的调节
  • 批准号:
    10202705
  • 财政年份:
    2018
  • 资助金额:
    $ 35.42万
  • 项目类别:
Regulation of hematopoiesis by CUX1
CUX1 对造血的调节
  • 批准号:
    10418712
  • 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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