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.
抽象的 尽管对化疗的初始反应频繁,但癌症患者的总体治愈率仍低于 20% AML 过去 45 年以来,复发仍然是最常见的死亡原因。最近的证据有 结果表明,HSC 中逐步遗传和表观遗传变化的积累导致了前- 白血病干细胞(前 LSC)不仅在疾病起源中发挥着关键作用,而且在白血病中也发挥着关键作用 复发。虽然这种癌前细胞状态的存在和必要性已在小鼠中得到证实 对于人类和 LSC 前形成和进展的分子机制知之甚少。 转录因子 PU.1 在 AML 患者中经常发生杂合突变或以其他方式受损。 我们最近报道了一种从分子驱动的白血病前期到 AML 进展的小鼠模型 杂合 PU.1 增强子缺失。这种新颖的模型的特点是可定义的、功能改变的预 白血病干细胞在关键分子、细胞生物学和表型方面与人类疾病非常相似 特征,包括疾病异质性。该模型现在允许识别和功能研究 驱动白血病前干细胞形成和进展的机制。此外,我们还获得了 概念证明 PU.1 低 AML 细胞表现出对进一步 PU.1 抑制的脆弱性增加(如 PU.1完全丧失会导致干细胞和造血功能衰竭),我们开发了一流的小型- PU.1 的分子药理学抑制剂,直接干扰 PU.1-染色质结合。引人注目的是, 我们发现shRNA或小分子抑制PU.1对AML细胞有显着的抑制作用, 包括白血病起始细胞水平,而对正常 HSC 的影响极小。 PU.1抑制 因此代表了一种针对 AML 的新的潜在策略。 根据我们最近的发现,我们建议: 1. 确定并研究对预治疗具有重要功能的途径。 LSC的形成和维护; 2. 确定触发白血病前期到白血病“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),从而引起疾病 异质性; 3. 研究抑制PU.1在AML细胞中抗白血病作用的机制。 我们将采用我们的新型小鼠 AML preLSC-to-LSC 过渡模型以及原发性人类 MDS/AML 样品。我们将纵向研究干细胞水平的分子变化并进行功能测试 体外和体内候选途径失调。此外,我们将使用 shRNA 和我们的新药物来 确定 PU.1 靶点介导 AML 细胞中 PU.1 抑制的抗白血病作用。 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, 他们进展为完全转化的 AML。此外,我们的研究将扩展我们的概念验证和 了解 PU.1 抑制作为治疗 AML 和 LSC 前期的新治疗策略 水平,这是一种全新的 AML 方法,具有巨大的转化潜力。

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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  • 批准号:
    3556971
  • 财政年份:
    1980
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    $ 44.01万
  • 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
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  • 批准号:
    3556968
  • 财政年份:
    1980
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ERADICATION OF ACUTE MYELOCYTIC LEUKEMIA CELLS BY MAB THERAPY
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