Microenvironmental Regulation of Leukemia Stem Cells

白血病干细胞的微环境调控

• 批准号: 9815760
• 负责人: RAVI BHATIA
• 金额: $ 35.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9815760
• 关键词: Aftercare; Bcr-Abl tyrosine kinase; Bone Marrow; Bone Marrow Cells; CXCL1 gene; CXCL12 gene; Cell Count; Cell Cycle; Cell Maintenance; Cell physiology; Cells; Chronic Myeloid Leukemia; Development; Disease remission; Drug resistance; EZH2 gene; Evaluation; Gene Expression; Genes; Goals; Growth; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; IL6 gene; IL8RB gene; Image; Immunologic Factors; Impairment; Inflammatory; Interleukin-1; Interleukin-8B Receptor; Ligands; Maintenance; Mediating; Natural regeneration; Oncogenic; Patients; Phosphotransferases; Play; Population; Protein Tyrosine Kinase; Recurrence; Regulation; Relapse; Research; Resistance; Role; Signal Transduction; Solid Neoplasm; Supporting Cell; TNF gene; Tyrosine Kinase Inhibitor; Up-Regulation; base; bcr-abl Fusion Proteins; cancer stem cell; cell growth; cell transformation; chemokine; chronic myeloid leukemia cell; cytokine; experience; genetic signature; hematopoietic stem cell quiescence; improved; leukemia; leukemia treatment; leukemic stem cell; mesenchymal stromal cell; mouse model; nestin protein; novel; novel strategies; patient subsets; prevent; progenitor; receptor; regenerative; self-renewal; stem cell fate; therapy resistant; transcriptome sequencing

PROJECT SUMMARY ABSTRACT Chronic myelogenous leukemia (CML) results from hematopoietic stem cell (HSC) transformation by the BCR- ABL oncogenic tyrosine kinase. Tyrosine kinase inhibitors (TKI) are highly effective in inducing remission and prolonging survival in CML patients, but do not eliminate primitive, quiescent leukemia stem cells (LSC) responsible for leukemia propagation and regeneration. As a result most patients experience rapid leukemia relapse after TKI discontinuation. However, a subset of patients achieving prolonged, deep remission can successfully discontinue TKI treatment without leukemia recurrence. Our research focuses on understanding mechanisms of LSC resistance to TKI, and development of strategies to target LSC and their microenvironment to prevent leukemia recurrence and enhance treatment free remission (TFR). We now understand that patients achieving TFR continue to harbor small numbers of BCR-ABL+ LSC, suggesting that microenvironmental or immune factor may regulate LSC potential to regenerate leukemia. The bone marrow (BM) microenvironment, which includes diverse hematopoietic and non-hematopoietic cells, plays a critical role in HSC regulation. In contrast, microenvironmental regulation of LSC growth is not well understood. Here we propose to characterize critical niche regulatory mechanisms for maintenance of LSC, and that may contribute to leukemia recurrence after stopping TKI treatment. We have shown that CML development leads to increased levels of several key inflammatory cytokines in the BM, which can provide a selective growth advantage to CML LSC. Our preliminary studies suggest that inflammatory signaling can modify CML BM MSC, resulting in enhanced support for CML LSC, and reduced support of normal HSC. In Aim 1, we will explore the role of TNFa in mediating alterations in BM MSC, resulting in increased expression of the inflammatory chemokine CXCL1 and enhanced signaling through CXCR2 receptor, in LSC maintenance and leukemia regeneration after TKI treatment. Multipotent mesenchymal stromal cells (MSC), identified on the basis of expression of LepR, nestin or Prx1, represent specialized BM niches that maintain normal HSC. Our preliminary studies show that CXCL12 deletion from Prx1+MSC leads to loss of LSC quiescence and enhanced sensitivity to TKI treatment. In Aim 2, we will investigate mechanisms of regulation of LSC cycling and treatment resistance by CXCL12-expressing BM MSC niches, focusing on regulation of EZH2 activity in LSC. We will also study the interaction between CXCL12 and inflammatory signaling in modifying MSC niche function. These studies will be conducted using murine models and primary human CML cells. Better understanding of mechanisms underlying microenvironmental regulation of malignant stem cells will help guide development of novel strategies to enhance TFR in CML patients. We further expect that the results of the proposed research will have broader implication towards other leukemias and solid tumors.

项目摘要 慢性粒细胞白血病（CML）是由BCR-1基因的造血干细胞（HSC）转化引起的。 ABL致癌酪氨酸激酶。酪氨酸激酶抑制剂（TKI）在诱导缓解和 延长CML患者的生存期，但不能消除原始的、静止的白血病干细胞（LSC） 负责白血病的繁殖和再生。因此，大多数患者经历快速白血病 停药后复发。然而，一部分达到长期深度缓解的患者可以 成功停止TKI治疗，无白血病复发。我们的研究重点是了解 LSC对TKI耐药的机制，以及针对LSC及其微环境的策略开发 预防白血病复发和增强免治疗缓解（TFR）。我们现在知道病人 实现TFR继续窝藏少量的BCR-ABL+ LSC，这表明微环境或 免疫因子可调节LSC再生白血病潜能。骨髓（BM）微环境， 包括不同的造血和非造血细胞，在HSC调节中起关键作用。在 相比之下，LSC生长的微环境调节还没有很好地理解。在这里，我们建议描述 维持LSC的关键生态位调节机制，可能有助于白血病复发 停止TKI治疗后。我们已经表明，CML的发展导致几个关键的水平增加， 在BM中的炎性细胞因子，这可以为CML LSC提供选择性生长优势。我们的初步 研究表明，炎症信号可以修饰CML BM MSC，从而增强对CML的支持， LSC，并减少正常HSC的支持。在目标1中，我们将探讨TNF α在介导细胞凋亡改变中的作用。 BM MSC，导致炎性趋化因子CXCL 1表达增加和信号传导增强 通过CXCR 2受体，在TKI治疗后的LSC维持和白血病再生中起作用。多能 基于LepR、巢蛋白或Prx 1的表达鉴定的间充质基质细胞（MSC）代表了 维持正常HSC的特殊BM龛。我们的初步研究表明，CXCL 12的缺失， Prx 1 +MSC导致LSC静止期的丧失和对TKI治疗的敏感性增强。在目标2中，我们将 研究表达CXCL 12 BM MSC调节LSC循环和治疗抗性的机制 小生境，侧重于LSC中EZH 2活性的调节。我们还将研究CXCL 12和 炎性信号转导在修饰MSC生态位功能中的作用。这些研究将使用鼠模型进行 和原代人CML细胞。更好地理解微环境调节的机制 恶性干细胞的研究将有助于指导提高CML患者TFR的新策略的开发。我们 我还希望这项研究的结果对其他白血病有更广泛的意义。 和实体瘤。