Modeling hematologic malignancy and self-renewal with gain-of-function MLL1

利用功能获得 MLL1 模拟血液恶性肿瘤和自我更新

基本信息

  • 批准号:
    8974958
  • 负责人:
  • 金额:
    $ 20.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-15 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Epigenetic regulators have recently received increasing attention as participants in pathogenic processes in human disease, as well as exciting new drug targets due to their enzymatic activities. A goal of this proposal is to generate an animal model in which a paradigmatic epigenetic regulator, MLL1, can be modulated to study a wide variety of human diseases in which this broadly-expressed protein plays an important role. This animal model utilizes Flp recombinase-directed integration to introduce an epitope-tagged, full-length MLL1 cDNA into embryonic stem cells in which doxycycline addition induces MLL1 cDNA expression. Roles for MLL1 in T-cell memory, neural stem cell specification, hematopoiesis, autism spectrum/cognitive disorders, Weideman- Steiner syndrome, skin and muscle stem cell function, neuroepithelial and hematologic cancers, vascular and craniofacial development have been established through a variety of individual approaches, however, the animal models to study the disease mechanisms have been lacking. In this proposal, we will generate an animal model that can accelerate discoveries in all of these fields. This model will be utilized by the co-PIs to test two major hypotheses. The proto-oncogene MLL1 is disrupted by chromosomal translocations or amplification in several types of leukemia with particularly poor prognosis. In contrast, loss of MLL1 in the hematopoietic system results in loss of self-renewal and proliferation defects in hematopoietic stem cells (HSCs). Based on our preliminary data, we will test the hypothesis that transient induction of MLL1 protein can enhance self-renewal in fetal and/or adult HSCs in a manner that could be clinically useful. Thus, the functional consequences of increased MLL1 levels will be determined using this model, particularly the effect on self- renewal and differentiation of HSCs. The impact on epigenetic modification of MLL1 target genes instrumental in self-renewal will be also be determined. The discovery of pathways that enhance self-renewal in HSCs may be directly relevant to efforts to treat umbilical cord blood or pluripotent sources of hematopoietic cells for transplantation. The second hypothesis is that chronic, sustained expression of wild-type MLL1 protein will lead to a myelodysplastic syndrome or leukemia. Our preliminary data illustrate that this Flp-mediated strategy using MLL1-fusion oncoproteins is feasible and can yield novel insights not possible with traditional retroviral- mediated MLL1-fusion leukemia models. Currently, there are no animal models in which MLL1 expression can be sustained in a manner that reflects gene amplification, thus no pre-clinical model for testing novel therapeutic strategies that may be effective in acute leukemia harboring MLL1 amplifications. Establishing the sufficiency of sustained MLL1 expression in myelodysplastic syndrome/leukemia will set the stage for testing the role of this epigenetic regulator in conjunction with other common mutations that occur in acute leukemia.
描述(由申请人提供):表观遗传调控因子作为人类疾病致病过程的参与者,以及由于其酶活性而令人兴奋的新药物靶点,最近受到越来越多的关注。这个提议的一个目标是生成

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Patricia Ernst其他文献

Patricia Ernst的其他文献

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{{ truncateString('Patricia Ernst', 18)}}的其他基金

Escape from CAR T surveillance through lineage plasticity
通过谱系可塑性逃避 CAR T 监控
  • 批准号:
    10419173
  • 财政年份:
    2022
  • 资助金额:
    $ 20.43万
  • 项目类别:
Escape from CAR T surveillance through lineage plasticity
通过谱系可塑性逃避 CAR T 监控
  • 批准号:
    10581656
  • 财政年份:
    2022
  • 资助金额:
    $ 20.43万
  • 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
  • 批准号:
    9814577
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
  • 批准号:
    10212374
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
Enhancing hematopoiesis through modulation of a histone methyltransferase: evaluating a new MLL1 gain-of-function animal model
通过调节组蛋白甲基转移酶增强造血功能:评估新的 MLL1 功能获得动物模型
  • 批准号:
    10017193
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
MLL Family Histone Methyltransferases in Myeloid Leukemia
髓系白血病中的 MLL 家族组蛋白甲基转移酶
  • 批准号:
    10406930
  • 财政年份:
    2018
  • 资助金额:
    $ 20.43万
  • 项目类别:
MLL Function in the Maintenance of the Blood Forming System
MLL 在维持造血系统中的功能
  • 批准号:
    8974685
  • 财政年份:
    2014
  • 资助金额:
    $ 20.43万
  • 项目类别:
MLL Function in the Maintenance of the Blood Forming System
MLL 在维持造血系统中的功能
  • 批准号:
    7867478
  • 财政年份:
    2009
  • 资助金额:
    $ 20.43万
  • 项目类别:
ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT
染色质调节因子 MLL 在 T 细胞发育中的作用
  • 批准号:
    7959994
  • 财政年份:
    2009
  • 资助金额:
    $ 20.43万
  • 项目类别:
ROLE OF THE CHROMATIN REGULATOR, MLL, IN T CELL DEVELOPMENT
染色质调节因子 MLL 在 T 细胞发育中的作用
  • 批准号:
    7720751
  • 财政年份:
    2008
  • 资助金额:
    $ 20.43万
  • 项目类别:

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