IGF/IGF1R signaling in hematopoiesis and leukemogenesis

造血和白血病发生中的 IGF/IGF1R 信号传导

• 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
• 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

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，增殖和凋亡方面起关键作用。 IGFS（IGF1和IGF2）和IGF1R都通常参与包括白血病在内的人类癌症。然而，对于该途径在正常造血的作用以及其激活如何促进白血病发生的知之甚少。癌症的发展高度依赖于细胞环境，该环境取决于受影响细胞中的固有遗传程序及其对微环境刺激的反应。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，这构成了开发新颖，更有效的靶向癌症疗法和预防癌症的基础。唐氏综合症急性巨型巨细胞白血病（DS-AMKL）和一种称为瞬态白血病（DS-TL）的相关pelekemic病态可作为研究此疾病。 DS-AMKL是一种独特的儿科白血病，其特征是胎儿起源的三合会，三体术和造血转录因子中的体细胞突变（GATA1）（导致产生较短的GATA1变体GATA1称为GATA1S）。通过分析GATA1S敲击蛋白小鼠和人DS-TL/DS-AMKL细胞，发现GATA1S会导致胎儿巨核细胞祖细胞（MPS）的过度增殖，而不是其成年对应物。胎儿MP高度依赖于IGF/IGF1R信号的增殖和存活，而成年MPS则没有。 GATA1S突变胎胎MP和白血病细胞均对IGF/IGF1R信号的抑制和激活过敏。基于这些初步数据，可以假设GATA1可以用作限制IGF/IGF1R信号传导（“发动机”）胎儿MP的刺激增殖的“制动”，这可能是通过抑制E2F靶基因的抑制，而GATA1在此功能中有缺陷。其他假设包括：过度活跃的IGF/IGF1R信号传导可能与体内的GATA1合作以启动DS-TL/DS-AMKL；胎儿和成人造血对IGF/IGF1R信号的要求可能不同，这是由某些类型的白血病所利用的特征，以驱动其恶性转化。提出了三个特定的目的来测试这些：（1）确定GATA1控制IGF/IGF1R信号传导的靶基因的分子机制（例如，E2F靶标，包括MYC，包括MYC）在胎儿巨核细胞中； （2）测试组成性活跃的IGF/IGF1R信号是否在体外和体内与GATA1S合作，以增强胎儿MPS的自我更新增殖。这将使用转基因方法在小鼠胎儿肝细胞中表达IGF2。 （3）通过有条件地在造血的不同阶段敲除IGF1R，以建立和比较IGF/IGF1R信号传导在胎儿与成人造型造血的作用。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以及其激活如何以细胞上下文依赖性方式有助于白血病的理解。 公共卫生相关性：该项目研究了一种主要的增长途径，IGF/IGF1R信号传导途径，在血液发育的不同阶段，并确定该途径在胎儿发育过程中是否以及该途径的过度活动与有缺陷的核调节蛋白合作，称为GATA1，称为GATA1，以启动在Down Down Downdrome syndrome Chyneldrome Childder中引发独特的白血病类型。长期的目标是基于对病原计划的更好理解，以细胞上下文依赖性的方式开发出新颖，更有效的靶向癌症疗法和癌症预防策略。