Microenvironmental Regulation of Leukemia Stem Cells

白血病干细胞的微环境调控

• 批准号: 9251763
• 负责人: RAVI BHATIA
• 金额: $ 30.5万
• 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 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251763
• 关键词: Adult; Adverse effects; Aftercare; Bcr-Abl tyrosine kinase; Biological Preservation; Bone Marrow; CXCL12 gene; Cell Compartmentation; Cell physiology; Cell surface; Cells; Chronic Myeloid Leukemia; Dasatinib; Development; Disease; Disease remission; Engraftment; Environment; Goals; Growth; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Homing; Imatinib; Inflammatory; Interleukin-1; Knowledge; Lead; Maintenance; Mesenchymal; Molecular; Patients; Pattern; Phenotype; Play; Population; Recurrence; Recurrent disease; Regulation; Relapse; Research; Residual state; Resistance; Resolution; Risk; Role; Sampling; Signal Transduction; Source; Stromal Cells; Therapeutic; Transgenic Organisms; Treatment Efficacy; Tyrosine Kinase Inhibitor; Withholding Treatment; abl Genes; base; bcr-abl Fusion Proteins; cell growth; chemokine; cytokine; improved; kinase inhibitor; leukemia; leukemic stem cell; leukemogenesis; mouse model; non-compliance; novel strategies; overexpression; prevent; public health relevance; response; self-renewal; targeted treatment

DESCRIPTION (provided by applicant): Chronic myelogenous leukemia (CML) is a lethal hematological malignancy that results from transformation of long-term hematopoietic stem cells (LTHSC) to leukemia stem cells (LSC) by the BCR-ABL gene. BCR- ABL tyrosine kinase inhibitors (TKI) are effective in inducing disease remission in CML patients and prolonging survival, but do not eliminate LSC responsible for disease propagation. CML patients currently require indefinite treatment with TKI to prevent disease recurrence, with associated risk of non-compliance, side effects, and considerable financial burden. There is a pressing need to develop strategies to target LSC to enable cessation of TKI treatment without leukemia recurrence. The major goal of our research is to achieve improved understanding of mechanisms regulating LSC growth to develop effective therapeutic strategies to target this resistant population. Our previous studies to characterize LSC in CML indicate that long-term engraftment and LSC capacity are restricted to cells with LTHSC surface markers. We have shown that, in addition to BCR-ABL induced alterations in LTHSC function, leukemia-induced alterations in the BM microenvironment results in differential regulation of leukemic and normal LTHSC, conferring a competitive growth advantage to leukemic LTHSC. Our results indicate that decreased expression of the chemokine CXCL12 by CML BM mesenchymal cells, in addition to contributing to reduced LTHSC homing and retention, may also support enhanced expansion of CML compared to normal LTHSC. We have also found that the pro-inflammatory cytokine IL-1? is overexpressed in CML BM, and that IL-1 signaling supports enhanced proliferation of CML compared to normal LTHSC. Abnormalities in BM microenvironmental regulation are improved but not completely corrected with TKI treatment. Here we will determine the contribution of these specific abnormalities in the CML BM microenvironment to the competitive growth advantage of CML LTHSC, and to the persistence of leukemic LTHSC after TKI treatment. In Specific Aim 1, we will examine mechanisms underlying reduced CXCL12 expression in CML BM mesenchymal subpopulations, and determine the role of reduced CXCL12 expression in the enhanced growth of CML compared to normal LTHSC in CML BM and in persistence of CML LTHSC following TKI treatment. In Specific Aim 2 we will examine mechanisms underlying IL-1? overexpression in CML BM following TKI treatment, and determine the role of IL-1? overexpression in enhanced growth of CML compared to normal LTHSC in CML BM and in persistence of CML LTHSC following TKI treatment. These studies will be performed using samples from CML patients as well as the SCL-tTA-BCR-ABL mouse model. The results of these studies will improve our understanding of interactions between leukemia cells and the BM microenvironment that regulate leukemic and normal LTHSC growth, and may guide development of novel strategies to enhance LSC targeting to achieve disease elimination and cure.

描述（由申请人提供）：慢性髓性白血病（CML）是一种致命的血液恶性肿瘤，由BCR-ABL基因将长期造血干细胞（LTHSC）转化为白血病干细胞（LSC）引起。BCR-ABL酪氨酸激酶抑制剂（TKI）可有效诱导CML患者的疾病缓解并延长生存期，但不能消除导致疾病传播的LSC。CML患者目前需要使用TKI进行无限期治疗以预防疾病复发，同时存在不依从性、副作用和相当大的经济负担的相关风险。迫切需要开发靶向LSC的策略，以使TKI治疗停止而不发生白血病复发。我们研究的主要目标是更好地了解LSC生长的调节机制，以开发针对这种耐药人群的有效治疗策略。我们以前的研究表明，慢性粒细胞白血病中的LSC的特点表明，长期植入和LSC的能力是有限的细胞与LTHSC的表面标志物。我们已经表明，除了BCR-ABL诱导的LTHSC功能改变，白血病诱导的BM微环境改变导致白血病和正常LTHSC的差异调节，赋予白血病LTHSC竞争性生长优势。我们的研究结果表明，CML BM间充质细胞趋化因子CXCL 12的表达减少，除了有助于减少LTHSC归巢和保留，也可能支持增强扩增CML相比，正常LTHSC。我们还发现，促炎细胞因子IL-1？在CML BM中过表达，并且IL-1信号传导支持CML与正常LTHSC相比增强的增殖。TKI治疗改善了BM微环境调节的异常，但未完全纠正。在这里，我们将确定这些特定的异常在CML BM微环境中的CML LTHSC的竞争性生长优势的贡献，和TKI治疗后的白血病LTHSC的持久性。在具体目标1中，我们将研究CML BM间充质亚群中CXCL 12表达降低的潜在机制，并确定与CML BM中正常LTHSC相比，CXCL 12表达降低在CML生长增强中的作用，以及TKI治疗后CML LTHSC的持续性。在具体目标2中，我们将研究IL-1？TKI治疗后CML BM中的过度表达，并确定IL-1？与CML BM中的正常LTHSC相比，在CML的生长增强和TKI治疗后CML LTHSC的持久性中的过表达。这些研究将使用CML患者样本以及SCL-tTA-BCR-ABL小鼠模型进行。这些研究的结果将提高我们对白血病细胞与调节白血病和正常LTHSC生长的BM微环境之间相互作用的理解，并可能指导开发新的策略，以增强LSC靶向以实现疾病消除和治愈。