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Eradicating leukemic stem cells in juvenile myelomonocytic leukemia

根除幼年粒单核细胞白血病中的白血病干细胞

基本信息

批准号：
10722045
负责人：
CHENG-KUI QU
金额：
$ 18.29万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722045
关键词：
Acceleration Address Adolescent Allogenic Antimalarials Area Cell Death Induction Cell Separation Cells Characteristics Childhood Clinical Clinical Research DNA Sequence Alteration Development Diagnosis Drug resistance Experimental Leukemia FDA approved Funding Opportunities Growth Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Hematopoietic System Hematopoietic stem cells Heterozygote Hyperactivity Impairment Juvenile Myelomonocytic Leukemia Knock-in Mouse Laboratories Maintenance Malignant Neoplasms Methodology Modeling Mus Mutant Strains Mice Mutate Mutation Myeloproliferative disease Outcome Pathogenesis Pathway interactions Patient Care Patients Penetrance Pharmaceutical Preparations Phase Population Prevention Prognosis Property Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Relapse Research Risk Role Signal Pathway Signal Transduction Signaling Protein Source Stem cell transplant Techniques Testing Therapeutic Therapeutic Effect Transplantation Treatment Failure Tyrosine Phosphorylation Work Xenograft Model anticancer research atovaquone cancer therapy early childhood inhibitor juvenile myelomonocytic leukemia cell leukemia leukemic stem cell mouse model mutant neoplastic cell novel novel strategies novel therapeutic intervention pharmacologic pre-clinical precursor cell response self-renewal standard of care stem cells therapeutic evaluation therapeutically effective tumor eradication tumor initiation

项目摘要

Project Summary Juvenile myelomonocytic leukemia (JMML), a clonal hematological malignancy of early childhood, has limited therapeutic options. While the current standard of care for patients with JMML relies on allogeneic stem cell transplant, relapse remains the main cause of treatment failure, most likely due to the persistence of leukemic stem cells (LSCs), a small population of self-renewing precursor cells that gives rise to the bulk of tumor cells. This reservoir of tumor cells is responsible for the long-term maintenance of leukemia growth and is also a major source of drug resistance. It remains a critical challenge to develop effective therapeutics to eradicate these tumor initiating cells. A novel treatment approach focused on the unique characteristics and vulnerabilities of LSCs is needed in order to address this problem. JMML is associated with genetic mutations in the signaling proteins involved in the Ras pathway, among which the protein tyrosine phosphatase Ptpn11 (Shp2), a positive regulator of Ras signaling, is most frequently mutated (heterozygous). These mutations cause greatly increased catalytic activity of Shp2, and JMML patients with Ptpn11 mutations have the worst prognosis in all subtypes of JMML. We created a line of conditional knock-in mice with the Ptpn11E76K mutation, the most common mutation found in JMML. Induction of the Ptpn11E76K/+ mutation in the hematopoietic system (Ptpn11E76K/+/Mx1-Cre+ mice) resulted in JMML-like myeloproliferative neoplasm (MPN) with full penetrance, suggesting a causative role of this mutation in the pathogenesis of JMML. With this unique mouse model, we have recently discovered that while the Ras/Erk signaling pathway was aberrantly enhanced, Stat3 activity as reflected by tyrosine phosphorylation (Tyr705) decreased by ~70% in Ptpn11E76K/+ mutant stem cells (referred to as LSCs since they could reproduce the same hematological malignancy in transplants) compared to that in wild-type (Ptpn11+/+/Mx1-Cre+) control stem cells. The decrease in Stat3 activity was apparently caused by the accelerated dephosphorylation of Stat3 by the hyperactive Shp2 E76K mutant because Stat3 is one of Shp2 substrate proteins. Importantly, Ptpn11E76K/+ LSCs appear to rely on Stat3 for self-renewal and maintenance - the deletion of Stat3 dramatically decreased the LSC pool in Ptpn11E76K/+/Mx1-Cre+/Stat3fl/fl double mutant mice. Consequently, these double mutant mice died rapidly, while none of Ptpn11E76K/+/Mx1-Cre+/Stat3+/+ or Ptpn11+/+/Mx1-Cre+/Stat3fl/fl single mutant mice did. The synthetic lethality induced by Stat3 deletion in Ptpn11 E76K mutant stem cells raises an intriguing possibility, that is, diminished Stat3 activity is an Achilles' heel of Ptpn11 mutated (Shp2 hyperactivated) LSCs, making them vulnerable to pharmacological inhibition of Stat3. We plan to test this hypothesis and accomplish the objective of this proposal by pursuing the following two aims. 1) To define the role of Stat3 in maintenance of LSCs in Ptpn11 (Shp2) mutated JMML. 2) To test the therapeutic effects of the Stat3 inhibitor atovaquone in the mouse model and patient cells-derived xenograft models of Ptpn11 associated JMML. This work may lead to a novel therapeutic strategy to deplete LSCs in this JMML subtype.

项目概要幼年型粒单核细胞白血病（JMML）是一种儿童早期的克隆性血液恶性肿瘤，其发病率有限。治疗选择。虽然目前 JMML 患者的护理标准依赖于同种异体干细胞移植后，复发仍然是治疗失败的主要原因，很可能是由于白血病的持续存在干细胞（LSC）是一小群自我更新的前体细胞，可产生大量肿瘤细胞。这种肿瘤细胞库负责白血病生长的长期维持，也是一个主要的耐药性的来源。开发有效的治疗方法来根除这些疾病仍然是一个严峻的挑战肿瘤起始细胞。一种新颖的治疗方法，重点关注以下疾病的独特特征和脆弱性：为了解决这个问题，需要 LSC。 JMML 与信号传导中的基因突变有关参与Ras途径的蛋白质，其中蛋白质酪氨酸磷酸酶Ptpn11（Shp2）是一种阳性蛋白 Ras 信号传导的调节因子，最常发生突变（杂合）。这些突变导致大大增加 Shp2 的催化活性，Ptpn11 突变的 JMML 患者在所有亚型中预后最差 JMML。我们创建了一系列带有 Ptpn11E76K 突变（最常见的突变）的条件敲入小鼠在 JMML 中找到。造血系统 Ptpn11E76K/+ 突变的诱导（Ptpn11E76K/+/Mx1-Cre+ 小鼠）导致具有完全外显率的 JMML 样骨髓增生性肿瘤 (MPN)，表明这种疾病的致病作用 JMML 发病机制中的突变。通过这种独特的小鼠模型，我们最近发现，虽然 Ras/Erk 信号通路异常增强，酪氨酸磷酸化反映了 Stat3 活性 (Tyr705) 在 Ptpn11E76K/+ 突变干细胞（称为 LSC，因为它们可以繁殖）中减少了约 70% 与野生型 (Ptpn11+/+/Mx1-Cre+) 对照相比，移植物中具有相同的血液恶性肿瘤干细胞。 Stat3活性的下降显然是由于Stat3去磷酸化加速造成的由于 Stat3 是 Shp2 底物蛋白之一，因此由过度活跃的 Shp2 E76K 突变体引起。重要的是，Ptpn11E76K/+ LSCs 似乎依赖 Stat3 进行自我更新和维护——Stat3 的删除显着降低了 Ptpn11E76K/+/Mx1-Cre+/Stat3fl/fl 双突变小鼠中的 LSC 池。结果，这些双突变小鼠死亡快速，而 Ptpn11E76K/+/Mx1-Cre+/Stat3+/+ 或 Ptpn11+/+/Mx1-Cre+/Stat3fl/fl 单突变小鼠则没有。这 Ptpn11 E76K 突变干细胞中 Stat3 缺失诱导的合成致死提出了一个有趣的可能性，即也就是说，Stat3 活性降低是 Ptpn11 突变（Shp2 过度激活）LSC 的致命弱点，使得它们易受 Stat3 的药理学抑制。我们计划检验这个假设并实现以下目标该提案旨在实现以下两个目标。 1）定义Stat3在Ptpn11中LSC维护中的作用 (Shp2) 突变的 JMML。 2) 测试Stat3抑制剂阿托伐醌在小鼠模型中的治疗效果以及 Ptpn11 相关 JMML 的患者细胞衍生异种移植模型。这项工作可能会写成一部小说消除该 JMML 亚型中 LSC 的治疗策略。