Mechanisms of Formation and Progression of Preleukemic Stem Cells

白血病前期干细胞的形成和进展机制

基本信息

  • 批准号:
    9890782
  • 负责人:
  • 金额:
    $ 44.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-04-01 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Despite frequent initial response to chemotherapy, overall cure rates have remained below 20% in patients with AML for the past 45 years, and relapse continues to be the most common cause of death. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in HSC lead to the formation of pre- leukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in leukemia relapse. While the existence and essentiality of such pre-cancerous cell states has been demonstrated in mice and humans, very little is known about the molecular mechanisms driving pre-LSC formation and progression. The transcription factor PU.1 is frequently heterozygously mutated or otherwise impaired in patients with AML. We have recently reported a mouse model of preleukemic-to-AML progression molecularly driven by heterozygous PU.1 enhancer deletion. This novel model is characterized by definable, functionally altered pre- leukemic stem cells and closely resembles human disease in key molecular, cell biological, and phenotypic features, including disease heterogeneity. This model now permits the identification and functional study of mechanisms driving the formation and progression of pre-leukemic stem cells. Furthermore, we have obtained proof-of-concept that PU.1-low AML cells show an increased vulnerability to further PU.1 inhibition (as complete loss of PU.1 leads to stem cell and hematopoietic failure), and we have developed first-in-class small- molecule pharmacologic inhibitors of PU.1, which directly interfere with PU.1-chromatin binding. Strikingly, we found that PU.1 inhibition by shRNA or small molecules has significant inhibitory effects on AML cells, including at the level of leukemia-initiating cells, while only minimally affecting normal HSC. PU.1 inhibition thus represents a new potential strategy to target AML. Based on our recent findings we propose to: 1. Identify and study pathways that are functionally critical for pre- LSC formation and maintenance; 2. Identify pathways that trigger the preleukemic-to-leukemic “switch”, and progression of pre-LSC to different AML subtypes (mature/immature/bi-lineage), thus causing disease heterogeneity; 3. Study the mechanisms underlying the anti-leukemic effects of PU.1 inhibition in AML cells. We will employ our novel murine AML preLSC-to-LSC transition model as well as primary human MDS/AML samples. We will longitudinally study molecular changes at the stem cell level and functionally test dysregulated candidate pathways in vitro and in vivo. Furthermore, we will use shRNA and our novel drugs to identify PU.1 targets that mediate the anti-leukemic effects of PU.1 inhibition in AML cells. In summary, our study will improve our molecular understanding of pre-cancerous/leukemic cell states and their progression to fully transformed AML. Furthermore, our study will extend our proof-of-concept and understanding of PU.1 inhibition as a novel therapeutic strategy for the treatment of AML and at the pre-LSC level, a completely new approach in AML with considerable translational potential.
摘要 尽管化疗最初的有效率很高,但患者的总体治愈率仍低于20%。 在过去的45年里,急性髓细胞白血病一直是最常见的死因,复发仍然是最常见的死因。最近的证据表明 研究表明,HSC的逐步遗传和表观遗传变化的积累导致了Pre-Pre的形成 白血病干细胞(Pre-LSC)不仅在疾病发生中发挥关键作用,而且在白血病中也发挥着关键作用 旧病复发。虽然在小鼠身上已经证明了这种癌前状态的存在和重要性 至于人类,人们对驱动前LSC形成和进展的分子机制知之甚少。 在AML患者中,转录因子PU.1经常发生杂合性突变或以其他方式受损。 我们最近报道了一种由分子驱动的白血病前期向AML进展的小鼠模型 杂合子PU.1增强子缺失。这种新的模型的特征是可定义的、功能改变的预 白血病干细胞,在关键分子、细胞生物学和表型上与人类疾病非常相似 特征,包括疾病的异质性。这一模型现在允许识别和功能研究 驱动白血病前期干细胞形成和发展的机制。此外,我们还获得了 概念验证:PU.1低的AML细胞表现出对进一步的PU.1抑制(AS)的易感性增加 完全丧失PU.1会导致干细胞和造血功能衰竭),我们已经开发出一流的小型 PU1的分子药理抑制剂,直接干扰PU1与染色质的结合。令人惊讶的是, 我们发现shRNA或小分子抑制PU1对AML细胞有显著的抑制作用, 包括在启动白血病的细胞水平上,而对正常的HSC只有最小的影响。PU.1抑制 这代表了针对AML的一种新的潜在战略。 根据我们最近的发现,我们建议:1.识别和研究在功能上对Pre-Pre至关重要的途径 LSC的形成和维持;2.确定触发白血病前期向白血病“转换”的途径,以及 前LSC进展为不同的AML亚型(成熟/未成熟/双系),从而导致疾病 研究PU1抑制AML细胞抗白血病作用的机制。 我们将使用我们的新的小鼠AML前LSC到LSC转换模型以及原代人类MDS/AML 样本。我们将纵向研究干细胞水平的分子变化并进行功能测试 体外和体内异常调控的候选通路。此外,我们将使用shRNA和我们的新药来 在急性髓系白血病细胞中确定介导PU1抑制抗白血病效应的PU1靶点。 总之,我们的研究将提高我们对癌前/白血病细胞状态的分子理解,并 他们进展为完全转变的急性髓系白血病。此外,我们的研究将扩展我们的概念验证和 对PU1抑制作为治疗AML和LSC前病变的新治疗策略的理解 级别,这是AML中一种全新的方法,具有相当大的翻译潜力。

项目成果

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Ulrich Steidl其他文献

Ulrich Steidl的其他文献

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{{ truncateString('Ulrich Steidl', 18)}}的其他基金

Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting
白血病前期干细胞的分子和细胞调控及其治疗靶向
  • 批准号:
    10478927
  • 财政年份:
    2021
  • 资助金额:
    $ 44.01万
  • 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
  • 批准号:
    10213515
  • 财政年份:
    2021
  • 资助金额:
    $ 44.01万
  • 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
  • 批准号:
    10571821
  • 财政年份:
    2021
  • 资助金额:
    $ 44.01万
  • 项目类别:
Contribution of macrophages in the HSC niche
巨噬细胞在 HSC 生态位中的贡献
  • 批准号:
    10374928
  • 财政年份:
    2021
  • 资助金额:
    $ 44.01万
  • 项目类别:
Molecular and Cellular Regulation of Pre-Leukemic Stem Cells and their Therapeutic Targeting
白血病前期干细胞的分子和细胞调控及其治疗靶向
  • 批准号:
    10299704
  • 财政年份:
    2021
  • 资助金额:
    $ 44.01万
  • 项目类别:
STAT3 inhibition as a therapeutic strategy against MDS stem cells
STAT3 抑制作为针对 MDS 干细胞的治疗策略
  • 批准号:
    10443583
  • 财政年份:
    2019
  • 资助金额:
    $ 44.01万
  • 项目类别:
STAT3 inhibition as a therapeutic strategy against MDS stem cells
STAT3 抑制作为针对 MDS 干细胞的治疗策略
  • 批准号:
    10206262
  • 财政年份:
    2019
  • 资助金额:
    $ 44.01万
  • 项目类别:
Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
  • 批准号:
    10199003
  • 财政年份:
    2018
  • 资助金额:
    $ 44.01万
  • 项目类别:
Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
  • 批准号:
    9982095
  • 财政年份:
    2018
  • 资助金额:
    $ 44.01万
  • 项目类别:
Therapeutic targeting of MDS stem cells
MDS 干细胞的治疗靶向
  • 批准号:
    9767250
  • 财政年份:
    2018
  • 资助金额:
    $ 44.01万
  • 项目类别:

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急性粒细胞白血病白血病干细胞动力学的计算分析
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  • 批准号:
    3556971
  • 财政年份:
    1980
  • 资助金额:
    $ 44.01万
  • 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
急性粒细胞白血病反应的决定因素
  • 批准号:
    3556968
  • 财政年份:
    1980
  • 资助金额:
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ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
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