IGF/IGF1R signaling in hematopoiesis and leukemogenesis

造血和白血病发生中的 IGF/IGF1R 信号传导

基本信息

批准号：
8086950
负责人：
Zhe Li
金额：
$ 37.76万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8086950
关键词：
Acute Megakaryocytic Leukemias Adult Affect Apoptosis Blood Blood Cells Bone Marrow Cell Line Cells Child Childhood Data Dependency Development Disease Down Syndrome Erythroid Fetal Development Fetal Liver GATA1 gene GATA1 protein Gene Targeting Genetic Programming Goals Growth Hematopoiesis Hematopoietic Hepatocyte Human IGF1 gene IGF1R gene IGF2 gene In Vitro Insulin-Like-Growth Factor I Receptor Knock-out Knowledge Lead Leukemic Cell Malignant - descriptor Malignant Neoplasms Megakaryocytes Megakaryocytopoieses Modeling Molecular Mus Mutation Nuclear Oncogenes Pathway interactions Play Population Prevention strategy Production Proteins Receptor Signaling Repression Role Signal Pathway Somatic Mutation Somatomedins Staging Stem cells Stimulus Testing Transgenic Organisms Triad Acrylic Resin Variant adult leukemia base cancer prevention cancer therapy cell growth cell type fetal genetic regulatory protein human GATA1 protein in utero in vivo leukemia leukemogenesis mutant novel progenitor programs response self-renewal stem transient myeloproliferative disorder

项目摘要

DESCRIPTION (provided by applicant): Insulin-like Growth Factor/Insulin-like Growth Factor 1 Receptor (IGF/IGF1R) signaling plays critical roles in regulating cell growth, proliferation and apoptosis. Both IGFs (IGF1 and IGF2) and IGF1R are commonly involved in human cancers, including leukemia. However, little is known about the role of this pathway in normal hematopoiesis and how its activation contributes to leukemogenesis. Cancer development is highly dependent on cellular context, which is determined by intrinsic genetic programs in the affected cells and by their responses to microenvironment stimuli. The long-term objective of this project is to understand the cell type-specific interplay of signaling pathways and oncogenes, which forms the basis for developing novel and more effective targeted cancer therapies and for cancer prevention. Down syndrome acute megakaryoblastic leukemia (DS-AMKL) and a related preleukemic condition called transient leukemia (DS- TL) are used as a model to study this. DS-AMKL is a unique pediatric leukemia characterized by the triad of fetal origin, trisomy 21, and somatic mutations in the hematopoietic transcription factor, GATA1 (leading to production of a shorter variant of GATA1 called GATA1s). By analyzing Gata1s knockin mice and human DS-TL/DS-AMKL cells, it was found that GATA1s leads to hyperproliferation of fetal megakaryocytic progenitors (MPs), but not their adult counterparts. Fetal MPs are highly dependent on IGF/IGF1R signaling for their proliferation and survival, whereas adult MPs are not. GATA1s mutant fetal MPs and leukemic cells are both hypersensitive to inhibition and activation of IGF/IGF1R signaling. Based on these preliminary data, it is hypothesized that GATA1 may serve as a "brake" to restrict the IGF/IGF1R signaling ("engine")-stimulated proliferation of fetal MPs, likely through repression of E2F target genes, whereas GATA1s is defective in this function. Additional hypotheses include: overactive IGF/IGF1R signaling may cooperate with GATA1s in vivo to initiate DS-TL/DS-AMKL; and fetal and adult hematopoiesis may have different requirements for IGF/IGF1R signaling, a feature capitalized upon by certain types of leukemia to drive their malignant transformation. Three specific aims are proposed to test these: (1) To determine the molecular mechanism by which GATA1 controls target genes of IGF/IGF1R signaling (e.g., E2F targets, including Myc) in fetal megakaryocytes; (2) To test whether constitutively active IGF/IGF1R signaling cooperates with GATA1s in vitro and in vivo to enhance the self-renewal proliferation of fetal MPs. This will be done using transgenic approaches to ectopically express IGF2 in mouse fetal liver cells; (3) To establish and to compare the in vivo role of IGF/IGF1R signaling in fetal versus adult stage hematopoiesis, by conditionally knocking out Igf1r at different stages of hematopoiesis. It is expected that these studies will significantly enhance our understanding of the role of IGF/IGF1R signaling in blood development, and of how its activation contributes to leukemia in a cellular context-dependent manner. PUBLIC HEALTH RELEVANCE: This project studies a major growth-promoting pathway, the IGF/IGF1R signaling pathway, in different stages of blood development, and determines whether and how overactivity of this pathway during fetal development cooperates with a defective nuclear regulatory protein called GATA1 to initiate a unique type of leukemia found in Down syndrome children. The long-term goal is to develop novel and more effective targeted cancer therapies and cancer preventive strategies based on a better understanding of pathogenic programs leading to cancer development in a cellular context-dependent manner.

描述（由申请人提供）：胰岛素样生长因子/胰岛素样生长因子1受体（IGF/IGF1R）信号传导在调节细胞生长、增殖和凋亡中发挥关键作用。 IGF（IGF1 和 IGF2）和 IGF1R 通常与人类癌症（包括白血病）有关。然而，人们对该途径在正常造血过程中的作用及其激活如何促进白血病发生知之甚少。癌症的发展高度依赖于细胞环境，这是由受影响细胞的内在遗传程序及其对微环境刺激的反应决定的。该项目的长期目标是了解信号通路和癌基因的细胞类型特异性相互作用，这为开发新颖且更有效的靶向癌症疗法和癌症预防奠定了基础。唐氏综合症急性巨核细胞白血病（DS-AMKL）和称为短暂性白血病（DS-TL）的相关白血病前期病症被用作研究这一问题的模型。 DS-AMKL 是一种独特的儿童白血病，其特征是胎儿起源三联体、21 三体性和造血转录因子 GATA1 的体细胞突变（导致产生 GATA1 的较短变体，称为 GATA1s）。通过分析 Gata1s 敲入小鼠和人类 DS-TL/DS-AMKL 细胞，发现 GATA1s 会导致胎儿巨核细胞祖细胞 (MP) 过度增殖，但不会导致成年巨核细胞祖细胞过度增殖。胎儿 MP 的增殖和存活高度依赖 IGF/IGF1R 信号传导，而成年 MP 则不然。 GATA1s 突变胎儿 MP 和白血病细胞都对 IGF/IGF1R 信号传导的抑制和激活高度敏感。基于这些初步数据，推测 GATA1 可能作为限制 IGF/IGF1R 信号（“引擎”）刺激的胎儿 MP 增殖的“制动器”，可能是通过抑制 E2F 靶基因来实现的，而 GATA1 在这个功能。其他假设包括：过度活跃的 IGF/IGF1R 信号传导可能与体内的 GATA1 协同启动 DS-TL/DS-AMKL；胎儿和成人的造血功能可能对 IGF/IGF1R 信号传导有不同的要求，某些类型的白血病利用这一特征来驱动其恶性转化。提出了三个具体目标来测试这些：（1）确定 GATA1 控制胎儿巨核细胞中 IGF/IGF1R 信号转导靶基因（例如 E2F 靶标，包括 Myc）的分子机制； (2) 检测组成型活性IGF/IGF1R信号是否在体外和体内与GATA1协同增强胎儿MP的自我更新增殖。这将通过转基因方法在小鼠胎儿肝细胞中异位表达 IGF2 来完成； (3) 通过在造血的不同阶段有条件地敲除 Igf1r，建立并比较 IGF/IGF1R 信号在胎儿阶段与成人阶段造血中的体内作用。预计这些研究将显着增强我们对 IGF/IGF1R 信号在血液发育中的作用的理解，以及其激活如何以细胞环境依赖性方式导致白血病。公共健康相关性：该项目研究血液发育不同阶段的主要生长促进途径，即 IGF/IGF1R 信号途径，并确定胎儿发育过程中该途径的过度活动是否以及如何与称为 GATA1 的有缺陷的核调节蛋白合作，以引发唐氏综合症儿童中发现的一种独特类型的白血病。长期目标是在更好地了解导致癌症以细胞环境依赖性方式发展的致病程序的基础上，开发新颖且更有效的靶向癌症治疗和癌症预防策略。