Functions of JARID2 in Normal and Neoplastic Hematopoiesis

JARID2 在正常和肿瘤造血中的功能

• 批准号: 10160649
• 负责人: Grant Anthony Challen
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160649
• 关键词: Acute Myelocytic Leukemia; Alleles; Biological Models; Blast Phase; CD34 gene; Cells; ChIP-seq; Chromosome 6; Chromosome Arm; Chromosome Deletion; Chronic; Clinical; Clonal Evolution; Co-Immunoprecipitations; Complex; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Disease Progression; Engraftment; Event; Evolution; Fright; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Hematological Disease; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Immunodeficient Mouse; Individual; Induced Mutation; Laboratories; Malignant - descriptor; Mass Spectrum Analysis; Modeling; Molecular; Morbidity - disease rate; Motivation; Mutation; Myelofibrosis; Myelogenous; Myeloproliferative disease; Neoplasm Metastasis; Null Lymphocytes; Oncogenic; Pathology; Patients; Phenotype; Polycomb; Prognosis; Reporting; Risk; Secondary to; Series; Signal Pathway; Signal Transduction; Site; Specificity; System; Techniques; Technology; Tertiary Protein Structure; Therapeutic; Time; Tumor Suppressor Proteins; bcr-abl Fusion Proteins; experimental study; functional genomics; genome sequencing; human model; improved; insight; interest; leukemic transformation; loss of function; mortality; mouse model; neoplastic; novel; novel therapeutic intervention; precision medicine; prevent; progenitor; programs; recruit; secondary outcome; self-renewal; stem cells; targeted treatment; transmission process

ABSTRACT Myeloproliferative neoplasms (MPNs) are clonal hematologic diseases characterized by the aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. More than 20,000 new patients are diagnosed in the USA each year, and in a substantial portion of these patients disease progression leads to transformation to secondary acute myeloid leukemia (sAML), a much more aggressive and therapeutically-refractive disease. Patients who develop sAML have a poor prognosis with an average survival time after transformation of less than five months. The clonal evolution of MPN to sAML is driven by acquisition of additional co-operating genetic mutations. While advances in genome sequencing technology have elucidated the genetic background of MPN, the contribution of specific genetic events to sAML transformation is not well understood and do not seem to be explained by the individual genetic alterations that characterize the disease. My laboratory has taken a particular interest in studying the mechanisms underlying post-MPN sAML transformation because the disease invariably proves fatal, and any findings that improve the diagnosis and treatment of these patients would represent a significant advance. One such event involves chromosomal deletions of the short arm of chromosome 6, which contains the JARID2 gene. We show conditional deletion of Jarid2 in mouse models accelerates development of MPN or leads to disease progression to sAML depending on the context, and genetic inhibition of JARID2 in CD34+ cells from MPN patients facilitates engraftment in immunodeficient mice and transmission of patient pathologies. Our preliminary data establish JARID2 as a bona fide hematopoietic tumor suppressor. The motivation for this proposal is to understand the mechanisms by which JARID2 exerts this function in MPN. We hypothesize that JARID2 functions as a hematopoietic tumor suppressor by restricting self-renewal in lineage-committed hematopoietic progenitor cells and restraining oncogenic JAK/STAT signaling. We will examine this through the following Specific Aims;  Determine the mechanisms by which JARID2 represses self-renewal in progenitors.  Define mechanisms through which JARID2 functions as a tumor suppressor.  Examine the unique requirement for JARID2 suppression in myelofibrosis. Understanding how JARID2 functions is critical for improving the clinical outcomes of sAML patients and identifying patients at risk for transformation, while also serving as a more general paradigm for genetic progression of MPN to sAML. In this proposal, we will leverage contemporary techniques with novel mouse models to comprehensively understand the mechanisms of how JARID2 functions as a tumor suppressor, and elucidate new precision medicine strategies for MPN and sAML patients.

摘要 骨髓增生性肿瘤（MPN）是一种克隆性血液病，其特征是异常的骨髓增生性肿瘤。 一种或多种骨髓谱系增殖和进行性骨髓纤维化。新增2万多个 在美国，每年都有100多名患者被诊断出来，在这些患者中， 进展导致转化为继发性急性髓细胞白血病（sAML），这是一种更具侵袭性的白血病。 和治疗折射性疾病。发生sAML的患者预后不良，平均 转化后存活时间少于5个月。MPN向sAML的克隆进化由以下驱动： 获得额外的合作基因突变。虽然基因组测序技术的进步 阐明了MPN的遗传背景，特定遗传事件对sAML的贡献 转化不是很清楚，似乎不能用个体遗传改变来解释， 描述疾病。我的实验室对研究 MPN后sAML转化，因为这种疾病总是证明是致命的，任何改善这种疾病的发现， 对这些患者的诊断和治疗将是一个重大的进步。其中一个事件涉及 6号染色体短臂的染色体缺失，其含有JARID 2基因。我们表明 小鼠模型中Jarid 2的条件性缺失加速了MPN的发展或导致疾病 根据背景进展为sAML，以及来自MPN的CD 34+细胞中JARID 2的遗传抑制 患者促进了在免疫缺陷小鼠中的植入和患者病理的传播。我们 初步数据确定JARID 2是真正的造血肿瘤抑制因子。这样做的动机 建议是了解JARID 2在MPN中发挥这一功能的机制。我们假设 JARID 2作为造血肿瘤抑制因子通过限制谱系定向的自我更新发挥作用 造血祖细胞和抑制致癌JAK/STAT信号传导。我们将通过 以下具体目标; 确定JARID 2抑制祖细胞自我更新的机制。 定义JARID 2作为肿瘤抑制因子的机制。 检查骨髓纤维化中JARID 2抑制的独特要求。 了解JARID 2的功能对于改善sAML患者的临床结局至关重要， 识别有转化风险的患者，同时也作为遗传学的更一般范式。 MPN进展为sAML。在这个提案中，我们将利用现代技术与新颖的鼠标 模型，以全面了解JARID 2如何作为肿瘤抑制因子发挥作用的机制， 阐明针对MPN和sAML患者的新的精准医学策略。