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.

儿童恶性肿瘤经常携带染色体臂水平拷贝数的变化，可能影响