Microenvironmental Regulation of Leukemia Stem Cells

白血病干细胞的微环境调控

• 批准号: 9047242
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047242
• 关键词: Adult; Adverse effects; Aftercare; Biological Preservation; Bone Marrow; Bone Marrow Cells; CXCL12 gene; Cell physiology; Cell surface; Cells; Chronic Myeloid Leukemia; Dasatinib; Development; Disease; Disease remission; Engraftment; Environment; Genes; Goals; Growth; Health; 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; Tyrosine Kinase Inhibitor; Withholding Treatment; base; bcr-abl Fusion Proteins; cell growth; chemokine; cytokine; improved; leukemia; leukemic stem cell; leukemogenesis; mouse model; non-compliance; novel strategies; overexpression; prevent; 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(申请人提供)：慢性粒细胞白血病(CML)是一种致命的血液系统恶性肿瘤，由bcr-abl基因将长期造血干细胞(LTHSC)转化为白血病干细胞(LSC)。BCR-ABL酪氨酸激酶抑制剂(TKI)能有效地诱导CML患者病情缓解和延长生存期，但不能消除导致疾病传播的LSC。CML患者目前需要接受TKI的无限期治疗以防止疾病复发，并伴随着不依从性、副作用和相当大的经济负担的相关风险。迫切需要制定针对LSC的策略，以便能够停止TKI治疗而不会复发白血病。我们研究的主要目标是更好地了解调节LSC生长的机制，以开发有效的治疗策略来针对这一耐药人群。我们先前对慢性粒细胞白血病中LSC的研究表明，长期植入和LSC能力仅限于具有LTHSC表面标记的细胞。我们已经证明，除了BCR-ABL诱导的LTHSC功能改变外，白血病诱导的骨髓微环境改变导致白血病和正常LTHSC的不同调节，赋予白血病LTHSC竞争生长优势。我们的结果表明，CML BM间充质细胞表达趋化因子CXCL12的减少，除了有助于减少LTHSC的归巢和滞留外，还可能支持与正常LTHSC相比，CML的增强扩张。我们还发现促炎细胞因子IL-1？IL-1信号在CML BM中高表达，与正常LTHSC相比，IL-1信号支持CML增殖增强。TKI治疗可以改善骨髓微环境调节的异常，但不能完全纠正。在这里，我们将确定这些特殊的CML骨髓微环境异常对CML LTHSC的竞争生长优势以及TKI治疗后白血病LTHSC的持久性的贡献。在特定的目标1中，我们将研究CML BM间充质亚群中CXCL12表达降低的机制，并确定CXCL12表达降低在CML BM中与正常LTHSC相比促进CML生长以及在TKI治疗后CML LTHSC持续中的作用。在具体目标2中，我们将研究IL-1的潜在机制？TKI治疗后CML BM过度表达及IL-1的作用？在CML BM中，与正常LTHSC相比，CML BM中高表达的LTHSC生长增强，在TKI治疗后CML LTHSC持续存在。这些研究将使用CML患者的样本以及SCL-TTA-BCR-ABL小鼠模型进行。这些研究结果将加深我们对白血病细胞与调节白血病和正常LTHSC生长的骨髓微环境之间相互作用的理解，并可能指导开发新的策略来增强LSC的靶向性，以实现疾病的消除和治愈。