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 尽管对化疗有频繁的初始反应,但在患有癌症的患者中, AML在过去的45年里,复发仍然是最常见的死亡原因。最近的证据 表明HSC中逐步遗传和表观遗传变化的积累导致前- 白血病干细胞(pre-LSC)不仅在疾病起源中而且在白血病中起关键作用 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, 与人类相比,对驱动前LSC形成和进展的分子机制知之甚少。 转录因子PU.1在AML患者中经常发生异源突变或以其他方式受损。 我们最近报道了一种由白血病前期向AML进展的小鼠模型, 杂合PU.1增强子缺失。这种新的模型的特点是可定义的,功能改变的前, 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 包括疾病异质性。该模型现在允许识别和功能研究 白血病前干细胞的形成和发展的驱动机制。此外,我们还获得了 概念证明,PU.1低AML细胞显示出对进一步PU.1抑制的增加的脆弱性(如 PU.1的完全丧失导致干细胞和造血功能衰竭),我们已经开发出一流的小- PU.1的分子药理学抑制剂,其直接干扰PU.1-染色质结合。引人注目的是, 我们发现通过shRNA或小分子抑制PU.1对AML细胞具有显著的抑制作用, 包括在白血病起始细胞的水平,而仅最低限度地影响正常HSC。PU.1抑制 因此代表了针对AML的新的潜在策略。 根据我们最近的研究结果,我们建议:1。确定和研究对预处理功能至关重要的途径, LSC的形成和维护; 2。识别触发白血病前期到白血病“转换”的途径, 前LSC进展为不同的AML亚型(成熟/不成熟/双系),从而导致疾病 异质性; 3.研究PU.1抑制剂在AML细胞中抗白血病作用的机制。 我们将采用我们的新型鼠AML preLSC向LSC转化模型以及原发性人MDS/AML模型。 样品我们将在干细胞水平上纵向研究分子变化, 在体外和体内失调的候选途径。此外,我们将使用shRNA和我们的新药, 鉴定在AML细胞中介导PU.1抑制的抗白血病作用的PU.1靶标。 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, 发展为完全转化的AML此外,我们的研究将扩展我们的概念验证, 了解PU.1抑制作为治疗AML和pre-LSC的新型治疗策略 这是一种全新的AML治疗方法,具有相当大的转化潜力。

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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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
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    $ 44.01万
  • 项目类别:
DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
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    3556968
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    1980
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