The Role of the APC Tumor Suppressor Gene in Hematopoiesis and Leukemogenesis

APC肿瘤抑制基因在造血和白血病发生中的作用

• 批准号: 8447589
• 负责人: Zhijian Qian
• 金额: $ 30.62万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447589
• 关键词: 5q23; APC gene; Acute Myelocytic Leukemia; Adult; Affect; Aftercare; Alkylating Agents; Alleles; Anemia; Apoptosis; Cell Cycle; Cell Therapy; Cell physiology; Cells; Characteristics; Chromosome Band; Chromosome Deletion; Chromosomes, Human, Pair 5; Data; Defect; Development; Differentiation and Growth; Disease; Disease model; Dose; Dysmyelopoietic Syndromes; Erythroid; Event; Frequencies; Functional disorder; Future; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; In Vitro; Ineffective Hematopoiesis; Knockout Mice; Large Intestine Carcinoma; Light; Maintenance; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Leukemia; Pancytopenia; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Play; Predisposition; Regulation; Role; Stem cells; Testing; Therapeutic; Therapy-Related Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome; Tumor Suppressor Genes; Tumor Suppressor Proteins; arm; base; chromosome 5 loss; chromosome 5q loss; cohort; exhaustion; in vivo; interest; leukemia; leukemogenesis; migration; mouse model; novel; novel therapeutics; prevent; progenitor; public health relevance; self-renewal; stem

DESCRIPTION (provided by applicant): Emerging evidence suggests that cancers are derived from cancer-initiating cells that originate from normal stem cells or progenitors. However, the molecular basis by which a normal stem or progenitor cell is transformed into a cancer-initiating cell is still poorly understood. The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis with a high rate of leukemic transformation. The APC tumor suppressor gene is involved in the development of colorectal carcinoma. A deletion of the long arm of chromosome 5 or loss of a whole chromosome 5, -5/del(5q), occurs at a high frequency in patients with primary MDS (10-15%) or therapy-related MDS (t-MDS) and therapy-related acute myeloid leukemia (t-AML) (40%). The APC gene is located on chromosome band 5q23, and is deleted >95% of patients with -5/del(5q), raising the question of whether APC acts as a tumor suppressor in the hematopoietic system. To examine the role of Apc in the function of HSCs and in normal hematopoiesis, we examined mice with a conditional Apc allele, and showed that inactivation of Apc in hematopoietic cells in vivo leads to rapid lethality due to bone marrow failure. In addition, loss of Apc results in enhanced cell cycle entry and increased apoptosis of HSCs and progenitor cells (HPCs), leading to rapid exhaustion of the HSC and HPC pool. These studies suggest that Apc is required for the function of HSCs and HPCs, and normal adult hematopoiesis. Additionally, in a pilot study, we showed that a cohort of mice with inactivation of a single allele of Apc in hematopoietic cells succumb to a severe anemia with macrocytosis, recapitulating several characteristic features of MDS and t-MDS with -5/del(5q). These features suggest that Apc haploinsufficient mice represent a novel and interesting disease model for MDS and t-MDS/t-AML with a -5/del(5q). We hypothesize that haploinsufficiency of APC contributes to the initiation and development of hematological malignancies through deregulation of the maintenance and the function of HSCs and HPCs. This hypothesis will be tested in three specific aims: (1) To determine whether haploinsufficiency of Apc contributes to the pathogenesis of hematological disorders via deregulation of the function of HSCs and myeloid progenitors; (2) To identify the genetic alterations that cooperate with haploinsufficiency of Apc in the transformation of HSCs into leukemia-initiating cells (LICs); and (3) To evaluate whether inhibition of the Wnt//2-catenin pathway prevents hematological disorders induced by inactivation of one or both alleles of Apc in vivo, and rescues the growth and differentiation defects of myeloid leukemia cells from t-MDS/t-AML patients with a -5/del(5q) ex vivo. The Apc haploinsufficient model provides us with a unique opportunity to study the molecular events that occur during the initiation of transformation of a normal stem or progenitor cell into a LIC, leading to the development of new effective therapeutic strategies targeting leukemia-initiating cells for MDS and t-MDS/t- AML with a -5/del(5q).

描述（由申请人提供）：新出现的证据表明，癌症源自于起源于正常干细胞或祖细胞的癌症起始细胞。然而，正常干细胞或祖细胞转化为癌症起始细胞的分子基础仍然知之甚少。骨髓增生异常综合征（MDS）是造血干细胞（HSCs）克隆性疾病，以造血功能低下和白血病转化率高为特征。APC抑癌基因参与大肠癌的发生发展。5号染色体长臂缺失或整个5号染色体缺失，-5/del（5 q），在原发性MDS（10-15%）或治疗相关MDS（t-MDS）和治疗相关急性髓性白血病（t-AML）（40%）患者中发生率很高。APC基因位于染色体带5 q23上，并且>95%的具有-5/del（5 q）的患者缺失，这提出了APC是否在造血系统中充当肿瘤抑制剂的问题。为了研究Apc在HSC功能和正常造血中的作用，我们检查了具有条件性Apc等位基因的小鼠，并表明体内造血细胞中Apc的失活导致由于骨髓衰竭而导致的快速致死。此外，Apc的丧失导致HSC和祖细胞（HPC）的细胞周期进入增强和凋亡增加，导致HSC和HPC池的快速耗尽。这些研究表明，Apc是HSC和HPC的功能以及正常成人造血所必需的。此外，在一项初步研究中，我们发现造血细胞中Apc的单个等位基因失活的一组小鼠死于严重贫血伴大红细胞症，重现了MDS和具有-5/del（5 q）的t-MDS的几个特征。这些特征表明Apc单倍不足小鼠代表了MDS和t-MDS/t-AML的一种新的和有趣的疾病模型，具有-5/del（5 q）。我们推测APC的单倍不足通过对HSC和HPC的维持和功能的失调而导致血液恶性肿瘤的发生和发展。本研究将从三个方面对这一假说进行验证：（1）确定Apc单倍不足是否通过HSC和髓系祖细胞的功能失调参与血液系统疾病的发病机制;（2）鉴定在HSC向白血病起始细胞（LICs）转化过程中与Apc单倍不足协同作用的遗传改变;以及（3）评估Wnt//2-连环蛋白途径的抑制是否在体内预防由Apc的一个或两个等位基因失活诱导的血液学病症，以及在体外挽救来自具有α-5/del（5 q）的t-MDS/t-AML患者的髓性白血病细胞的生长和分化缺陷。Apc单倍不足模型为我们提供了一个独特的机会来研究在正常干细胞或祖细胞转化为LIC的起始过程中发生的分子事件，从而导致针对MDS和具有-5/del（5 q）的t-MDS/t-AML的白血病起始细胞的新的有效治疗策略的开发。