Microenvironmental Regulation of Leukemia Stem Cells

描述（由申请人提供）：慢性骨髓性白血病（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）引起。BCR- ABL酪氨酸激酶抑制剂（TKI）可有效诱导CML患者疾病缓解并延长生存期，但不能消除负责疾病传播的LSC。CML患者目前需要无限期地使用TKI治疗以预防疾病复发，这伴随着不依从性风险、副作用和相当大的经济负担。迫切需要制定针对LSC的策略，以使停止TKI治疗而不复发白血病。我们研究的主要目标是提高对LSC生长调节机制的理解，以制定针对这种耐药人群的有效治疗策略。我们之前对CML中LSC特征的研究表明，LSC的长期移植和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BM微环境改变导致白血病LTHSC和正常LTHSC的差异调节，赋予白血病LTHSC竞争生长优势。我们的研究结果表明，CML - BM间充质细胞趋化因子CXCL12的表达减少，除了有助于减少LTHSC的归巢和保留外，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？在CML BM中过表达，并且与正常LTHSC相比，IL-1信号支持CML的增殖增强。脑基微环境调节异常得到改善，但TKI治疗不能完全纠正。在这里，我们将确定CML - BM微环境中这些特异性异常对CML - LTHSC竞争性生长优势的贡献，以及TKI治疗后白血病性LTHSC的持久性。在Specific Aim 1中，我们将研究CML - BM间质亚群中CXCL12表达降低的机制，并确定与CML - BM中正常LTHSC相比，CXCL12表达降低在CML - BM中促进CML生长和TKI治疗后CML - LTHSC持续存在中的作用。在特异性目标2中，我们将研究IL-1的机制。TKI治疗后CML - BM中IL-1的过表达，并确定IL-1的作用。在CML - BM中，与正常LTHSC相比，CML的生长增强以及TKI治疗后CML - LTHSC的持续存在中存在过表达。这些研究将使用来自CML患者的样本以及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来增强LSC靶向，从而实现疾病的消除和治愈。

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.