Flt3: Role in Leukemia Stem Cells

Flt3：在白血病干细胞中的作用

• 批准号: 8212932
• 负责人: DONALD SMALL
• 金额: $ 30.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212932
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Bone Marrow; Cancer Biology; Cells; Data; Dependence; Development; Event; FLT3 gene; FLT3 inhibitor; Generations; Genes; Genetic; Hematopoietic; Hematopoietic Stem Cell Transplantation; Heterogeneity; Human; Induced Mutation; Knock-in Mouse; Laboratories; Lesion; Leukemic Cell; Modeling; Mus; Mutate; Mutation; Myeloproliferative disease; Oncogenes; Other Genetics; Patients; Play; Population; Predisposition; 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; stem cell biology; stem cell population; 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.

在过去几年中，癌症生物学领域的研究已经证明了癌症的重要性。 干细胞，其中许多最有力的数据来自白血病干细胞（LSC）的研究。LSCs 在许多方面与大量的白血病细胞明显不同。这些细胞负责 随着时间的推移白血病的延续。为了根除患者的白血病，有必要消除 这些细胞。对这些细胞更全面的了解可能会提高我们靶向它们的能力， 提高各种白血病的治愈率。 FLT 3是一种受体酪氨酸激酶，在急性炎症中频繁突变为组成性激活形式。 骨髓性白血病（AML），以及较不常见的急性淋巴细胞白血病（ALL）。许多研究 这些突变导致AML患者预后不良。我们的长期目标是更好地 了解这种经常突变的癌基因如何促进白血病的发生， 改善FLT 3发挥作用的AML和ALL患者的治疗。我们已执行 表明这些突变通常存在于原发性AML的功能性LSC中的实验 样品我们现在打算研究这种癌基因如何促进LSC生物学。 为此，我们开发了一种小鼠模型，在该模型中，我们将FLT 3/ITD突变插入到小鼠中。 小鼠FLT 3基因。因此，这种FLT 3/ITD“敲入”小鼠表达组成性激活的癌基因 在正常的FLT 3启动子的控制下，从而以适当的水平和在 合适的细胞群体。这些小鼠在所有小鼠中均发生骨髓增生性疾病， 经常是AML。我们将研究其他已知的癌基因如何在患者中与FLT 3相关 突变与突变FLT 3协同将造血干祖细胞转化为LSC。我们将 确定LSC如何响应FLT 3酪氨酸激酶抑制剂（TKI）和化疗，以增加 我们对这些白血病为何如此难以治愈的理解。 我们还将利用NOD-scid小鼠研究FLT 3突变型AML患者的LSC，以观察其是否与FLT 3突变型AML患者的LSC相似。 FLT 3突变在短期和长期LSC中表达。我们将对移植了LSC的小鼠进行治疗， 已经通过慢病毒插入FLT 3 TKI和化疗标记， LSC中对FLT 3信号传导依赖的异质性是耐药的可能原因。 Lay描述：FLT 3是急性髓细胞白血病中最常见的突变基因， 突变几乎没有治愈的机会。在本提案中，我们将研究FLT 3在LSC生物学中的作用， 开发更好的治疗方法来提高这些患者的治愈率。