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
• 负责人: Megan McNerney
• 金额: $ 36.51万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10229402
• 关键词: AML/MDS; Address; Adolescent; Anemia; Automobile Driving; Binding; Blood; Blood Cells; CRISPR/Cas technology; Cancer Survivor; Chemotherapy and/or radiation; Child; Childhood; Childhood Acute Myeloid Leukemia; Chromosome 7; Chromosome Arm; Chromosome abnormality; Chromosomes; Complement; Data; Development; Disease; Dysplasia; EZH2 gene; Engineering; Epigenetic Process; Etiology; Future; Gene Deletion; Genes; Genetic; Genetic Epistasis; Genetic Models; Goals; Growth; Hematopoietic; In Vitro; Infiltration; Inherited; Juvenile Myelomonocytic Leukemia; Laboratories; Malignant Childhood Neoplasm; Modeling; Molecular; Mus; Mutate; Mutation; Myelodysplastic/Myeloproliferative Disease; Myelogenous; Myeloproliferative disease; Neoplasms; Oncogenic; Other Genetics; Outcome; Pathogenesis; Pathway interactions; Patients; Penetrance; Pharmaceutical Preparations; Physiological; Prognosis; Recurrence; Reporting; Research Personnel; Role; Signal Transduction; Site; Syndrome; Testing; Transcriptional Regulation; Tumor Suppressor Genes; Work; cancer predisposition; cell growth; childhood cancer survivor; chromosome 7 loss; chromosome 7q loss; combinatorial; design; dosage; early childhood; genome editing; high risk; histone methyltransferase; homeodomain; human disease; improved outcome; in vivo; knock-down; leukemia; leukemogenesis; molecular targeted therapies; mouse model; new therapeutic target; novel therapeutics; pre-clinical; programs; screening; self-renewal; side effect; stem cell survival; therapeutic target; therapy resistant; transcription factor; treatment response; tumor; tumorigenesis

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.

小儿恶性肿瘤经常怀有染色体臂级拷贝数的变化，可能会影响 大量基因的表达水平，但是分段改变如何促进肿瘤发生 仍然定义很差。这是我们对儿童癌症发病机理的理解的主要差距 并阻碍了新疗法的合理设计。这样的删除之一是损失零件或所有染色体7 [-7/del（7q）]，这是儿童时期髓样恶性肿瘤中最常见的细胞遗传学异常。 -7/del（7q）发生 多达33％的青少年脊髓细胞性白血病（JMML）是侵略性骨髓增生的 综合征/脊髓增生性肿瘤（MDS/MPN），其特征是RAS途径突变和其他少数其他 体细胞改变。在髓样恶性肿瘤中，-7/del（7q）与治疗耐药性和差有关 预后的原因尚不理解。该提议的长期目标是了解 -7/DEL（7Q）的分子发病机理，并揭示了JMML患者的新治疗靶标。在上一个 工作，我们报道了转录因子CUX1是一种高度保守的髓样肿瘤基因 编码在7Q。我们证明了致癌性RAS途径突变与CUX1的惊人关联 跨肿瘤类型的缺失。我们最近设计了一个Cux1敲低鼠标模型（Cux1low），该模型 开发具有人类JMML功能的自发MDS/MPN，包括所有的脊髓细胞膨胀 造血区室内浸润到非杂造组织，所有骨髓谱系中的发育异常， 和贫血。除CUX1外，7Q缺失通常很大，并且跨越了其他已建立或假定的肿瘤 抑制基因和/或髓样调节剂。在此提案中，我们将检验以下假设：7q是一个 “连续基因综合征”区域，其中多个基因的剂量失衡驱动JMML，在 结合致癌RAS信号传导。我们将使用我们独特的鼠标模型和CRISPR/CAS9基因组 编辑以实现以下特定目的：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理 JMML中的7Q基因。这项工作将对髓样恶性肿瘤领域产生积极影响：i） 阐明了7Q基因组合损失驱动疾病的分子机制； ii）识别 用于治疗JMML的新分子靶标； iii）建立生理精确的小鼠模型 其中可以快速测试和优化针对人类疾病的新疗法。我们的JMML鼠标模型 将满足童年髓样恶性肿瘤的主要未满足需求，特别是用于临床前的鼠标模型 在未来的研究中筛选批准和实验药物。我们的工作将揭示相关的增殖 和治疗靶标在此模型中测试的分化途径。