Functions of JARID2 in Normal and Neoplastic Hematopoiesis

摘要 骨髓增生性肿瘤(MPN)是一种以异常为特征的克隆性血液病 一个或多个髓系的增殖和进行性骨髓纤维化。新增20,000多个 在美国，每年都有患者被确诊，其中很大一部分患者患有疾病 进展导致转化为继发性急性髓系白血病(SAML)，一种更具侵袭性的疾病 以及治疗性屈光不正疾病。罹患SAML的患者预后较差，平均 改造后存活时间不到5个月。MPN向SAML的克隆进化是由 获得更多共同操作的基因突变。虽然基因组测序技术的进展 阐明了MPN的遗传背景、特定遗传事件对SAML的贡献 转化还没有被很好地理解，似乎也不能用个体的基因改变来解释 描述这种疾病的特征。我的实验室特别感兴趣的是研究 MPN后SAML转化，因为这种疾病总是被证明是致命的，任何可以改善 这些患者的诊断和治疗将是一个重大的进步。其中一个这样的事件涉及 含有JARID2基因的6号染色体短臂的染色体缺失。我们展示了 小鼠模型中Jarid2的条件性缺失加速MPN的发展或导致疾病 MPN对CD34+细胞中JARID2基因的抑制作用 患者促进了免疫缺陷小鼠的植入和患者病理的传播。我们的 初步数据证实JARID2是一种真正的造血肿瘤抑制因子。这样做的动机是 建议理解JARID2在MPN中发挥这一功能的机制。我们假设 JARID2通过限制谱系承诺的自我更新而发挥造血肿瘤抑制因子的作用 造血祖细胞和抑制致癌JAK/STAT信号转导。我们将对此进行深入研究 以下是具体目标； 决定了JARID2抑制祖细胞自我更新的机制。 定义了JARID2作为肿瘤抑制因子发挥作用的机制。 检查了骨髓纤维化中对JARID2抑制的独特要求。 了解JARID2的功能对于改善SAML患者和 识别有转化风险的患者，同时也作为基因研究的更一般范例 从MPN到SAML的进展。在这个提案中，我们将利用现代技术和新颖的鼠标 全面了解JARID2作为肿瘤抑制因子的机制的模型，以及 阐明针对MPN和SAML患者的新的精准医学策略。

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.