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源自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（HSC）的克隆性疾病，其特征是无效造血和高白血病转化率。 APC抑癌基因参与结直肠癌的发生发展。原发性 MDS (10-15%) 或治疗相关性 MDS (t-MDS) 患者中，5 号染色体长臂缺失或整个 5 号染色体丢失 (-5/del(5q)) 的发生频率较高）和治疗相关的急性髓系白血病（t-AML）（40%）。 APC基因位于染色体带5q23上，并且在-5/del(5q)患者中>95%被删除，这就提出了APC是否在造血系统中充当肿瘤抑制因子的问题。为了检查 Apc 在 HSC 功能和正常造血中的作用，我们检查了具有条件 Apc 等位基因的小鼠，结果表明，体内造血细胞中 Apc 失活会导致因骨髓衰竭而快速致死。此外，Apc 的缺失导致细胞周期进入增强，HSC 和祖细胞 (HPC) 凋亡增加，导致 HSC 和 HPC 池快速耗尽。这些研究表明 Apc 是 HSC 和 HPC 功能以及正常成人造血功能所必需的。此外，在一项初步研究中，我们发现造血细胞中 Apc 单个等位基因失活的一组小鼠会死于严重贫血伴大红细胞增多症，以 -5/del(5q) 重现 MDS 和 t-MDS 的几个特征）。这些特征表明，Apc 单倍体不足的小鼠代表了一种新颖且有趣的 MDS 和 t-MDS/t-AML 疾病模型，具有 -5/del(5q)。我们假设 APC 的单倍体不足通过 HSC 和 HPC 的维护和功能失调而导致血液恶性肿瘤的发生和发展。这一假设将在三个具体目标上得到检验：(1) 确定 Apc 的单倍体不足是否通过 HSC 和骨髓祖细胞功能失调而导致血液疾病的发病机制； (2) 鉴定在 HSC 转化为白血病起始细胞 (LIC) 过程中与 Apc 单倍体不足相配合的遗传改变； (3) 评估Wnt//2-catenin通路的抑制能否在体内预防由Apc的一个或两个等位基因失活引起的血液疾病，并挽救t-MDS/t骨髓性白血病细胞的生长和分化缺陷-离体具有-5/del(5q)的AML患者。 Apc 单倍体不足模型为我们提供了一个独特的机会来研究正常干细胞或祖细胞转化为 LIC 过程中发生的分子事件，从而开发出针对 MDS 和白血病起始细胞的新有效治疗策略。具有 -5/del(5q) 的 t-MDS/t- AML。