Flt3: Role in Leukemia Stem Cells

Flt3：在白血病干细胞中的作用

• 批准号: 7355828
• 负责人: DONALD SMALL
• 金额: $ 32.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355828
• 关键词: Acute; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Bone Marrow; Cancer Biology; Cells; Cellular biology; Data; Dependence; Development; Event; FLT3 gene; FLT3 inhibitor; Generations; Genes; Genetic; Hematopoietic; Heterogeneity; Human; Induced Mutation; Knock-in Mouse; Laboratories; Lesion; Leukemic Cell; Lymphoblastic Leukemia; Modeling; Mus; Mutate; Mutation; Myeloproliferative disease; Numbers; Oncogenes; Other Genetics; Patients; Play; Population; Predisposition; Rate; Receptor Protein-Tyrosine Kinases; Relapse; Research; Research Personnel; Resistance; Role; Sampling; Signal Transduction; Signal Transduction Pathway; Staging; Stem cells; Testing; Time; Tyrosine Kinase Inhibitor; cancer stem cell; chemotherapy; immunodeficient mouse model; improved; leukemia; leukemic stem cell; leukemogenesis; mouse model; mutant; outcome forecast; promoter; research study; response; stem; therapy resistant

Research in the field of cancer biology over the past few years has demonstrated the importance of cancer stem cells, with much of the strongest data emerging from the study of leukemia stem cells (LSCs). LSCs clearly differ from the bulk leukemic cells in a number of ways. These are the cells that are responsible for perpetuation of leukemia over time. In order to eradicate leukemia in a patient it is necessary to eliminate these cells. A fuller understanding of these cells is likely to improve our ability to target them, thereby improving the cure rate for a variety of leukemias. FLT3 is a receptor tyrosine kinase that is mutated frequently to a constitutively activated form in acute myeloid leukemia (AML) and, less frequently, in acute lymphoblastic leukemia (ALL). Many studies have shown that these mutations result in poor prognosis for AML patients. Our long-term objective is to better understand how this frequently mutated oncogene contributes to leukemogenesis in order to develop improved treatments for patients with AML and ALL in which FLT3 plays a role. We have performed experiments that indicate these mutations are usually present in the functional LSC from primary AML samples. We now propose to study how this oncogene contributes to LSC biology. Towards this end, we have developed a mouse model in which we inserted a FLT3/ITD mutation into the murine FLT3 gene. This FLT3/ITD "knock-in" mouse thus expresses the constitutively activated oncogene under the control of the normal FLT3 promoter and thus expresses it at the appropriate level and in the appropriate cell populations. These mice develop a myeloproliferative disorder in all mice and, less frequently, AML. We will study how other oncogenes known to occur in patients in association with FLT3 mutations cooperate with mutant FLT3 to transform hematopoietic stem-progenitor cells into LSCs. We will determine how the LSC responds to FLT3 tyrosine kinase inhibitors (TKI) and to chemotherapy to increase our understanding of why these leukemias are so difficult to cure. We will also utilize the NOD-scid mouse to study the LSC from patients with FLT3 mutant AML to see if the FLT3 mutation is expressed in the short- and long-term LSC. We will treat mice engrafted with LSCs that have been marked by lentiviral insertion with FLT3 TKI and chemotherapy so that we can study heterogeneity of dependence on FLT3 signaling in LSC as a possible cause of resistance. Lay description: FLT3 is the most frequently mutated gene in acute myeloid leukemia and patients with this mutation have little chance for cure. In this proposal we will study the role of the FLT3 in LSC biology in order to develop better therapies to improve the cure rate for these patients.

过去几年在癌症生物学领域的研究证明了癌症的重要性 干细胞，其中许多最有力的数据来自对白血病干细胞(LSCs)的研究。LSCS 明显不同于大量的白血病细胞在许多方面。这些细胞负责 随着时间的推移白血病的永久化。为了根除患者的白血病，有必要消除 这些细胞。对这些细胞的更全面的了解可能会提高我们针对它们的能力，从而 提高多种白血病的治愈率。 Flt3是一种受体酪氨酸激酶，在急性白血病中经常突变为结构性激活形式。 髓系白血病(AML)，较少见于急性淋巴细胞白血病(ALL)。许多研究都有 表明这些突变导致急性髓系白血病患者预后不良。我们的长期目标是更好地 了解这种频繁突变的癌基因如何促进白血病的发生 改进了对AML和ALL患者的治疗，Flt3在其中发挥了作用。我们已经表演了 实验表明，这些突变通常存在于原发AML的功能性LSC中 样本。我们现在建议研究该癌基因如何对LSC生物学做出贡献。 为此，我们开发了一种小鼠模型，在该模型中，我们将Flt3/ITD突变插入到 小鼠Flt3基因。这种Flt3/ITD“敲入”小鼠因此表达了结构性激活的癌基因 在正常的Flt3启动子的控制下，从而在适当的水平和在 合适的细胞群体。这些小鼠在所有小鼠中都出现了骨髓增殖性疾病，而且 通常是急性髓系白血病。我们将研究其他已知的癌基因是如何在与Flt3相关的患者中发生的 突变与突变的Flt3协同将造血干/祖细胞转化为LSCs。我们会 确定LSC对Flt3酪氨酸激酶抑制剂(TKI)和化疗的反应 我们对这些白血病为什么这么难治愈的理解。 我们还将利用NOD-SCID小鼠来研究来自Flt3突变AML患者的LSC，看看是否 Flt3突变在短期和长期LSC中均有表达。我们将治疗移植了LSCs的小鼠 已经通过慢病毒插入Flt3 TKI和化疗来标记，这样我们就可以研究 LSC对Flt3信号依赖的异质性可能是耐药的原因之一。 层描述：Flt3是急性髓系白血病中最常见的突变基因，其患者 突变几乎没有治愈的机会。在这项建议中，我们将研究Flt3在LSC生物学中的作用 开发更好的治疗方法，以提高这些患者的治愈率。