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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.

项目摘要幼年粒单核细胞白血病（JMML）是一种发生于儿童早期的克隆性血液恶性肿瘤，治疗选择虽然目前JMML患者的标准治疗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，最有可能是由于白血病的持续存在。干细胞（LSC），一小群自我更新的前体细胞，产生大量的肿瘤细胞。这种肿瘤细胞的储存库负责白血病生长的长期维持，也是白血病的主要原因。抗药性的来源。开发有效的治疗方法来根除这些疾病仍然是一个关键的挑战。肿瘤起始细胞一种新的治疗方法，重点是独特的特点和脆弱性，为了解决这一问题，需要地方供应链。JMML与信号传导中的基因突变有关，蛋白酪氨酸磷酸酶Ptpn 11（Shp 2），一个阳性的 Ras信号传导的调节子是最常突变的（杂合的）。这些突变导致 Shp 2和Ptpn 11突变的JMML患者的催化活性在所有亚型中具有最差的预后。 JMML。我们建立了一个条件性基因敲入小鼠品系，该品系带有Ptpn 11 E76 K突变，这是最常见的突变在JMML中找到。造血系统中Ptpn 11 E76 K/+突变的诱导（Ptpn 11 E76 K/+/Mx 1-Cre+小鼠）导致JMML样骨髓增生性肿瘤（MPN）完全转移，表明这一致病作用 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， Ras/Erk信号通路异常增强，Stat 3活性通过酪氨酸磷酸化反应，在Ptpn 11 E76 K/+突变干细胞（称为LSC，因为它们可以繁殖）中，Tyr 705的表达降低了约70 移植物中相同的血液学恶性肿瘤）与野生型（Ptpn 11 +/+/Mx 1-Cre+）对照相比干细胞Stat 3活性的降低显然是由于Stat 3的去磷酸化加速所致因为Stat 3是Shp 2的底物蛋白之一。重要的是，Ptpn 11 E76 K/+ LSC似乎依赖于Stat 3进行自我更新和维持-Stat 3的缺失显著降低了LSC的表达。 Ptpn 11 E76 K/+/Mx 1-Cre+/Stat 3fl/fl双突变小鼠中的LSC池。因此，这些双突变小鼠死亡而Ptpn 11 E76 K/+/Mx 1-Cre+/Stat 3 +/+或Ptpn 11 +/+/Mx 1-Cre+/Stat 3fl/fl单突变小鼠则不能。的在Ptpn 11 E76 K突变干细胞中，Stat 3缺失诱导的合成致死性提出了一种有趣的可能性， Stat 3活性降低是Ptpn 11突变（Shp 2过度活化）LSC的致命弱点，使它们容易受到Stat 3的药理学抑制。我们计划测试这一假设，并实现以下目标：这一建议通过追求以下两个目标。1)明确Stat 3在Ptpn 11中维持LSC中的作用（Shp 2）突变的JMML。2)为了测试Stat 3抑制剂阿托伐醌在小鼠模型中的治疗效果，和Ptpn 11相关JMML的患者细胞来源的异种移植物模型。这项工作可能会导致一部小说治疗策略，以消除这种JMML亚型中的LSC。