Mechanisms of Chronic Myeloid Leukemia Progenitor Cell Survival

许多慢性粒细胞白血病（CML）患者对伊马替尼（Gleevec）的反应非常好。 然而，复发是停药后的规律，与药物存在下完全致白血病的CML祖细胞的存活一致。因此，治疗必须持续终身，尽管往往有显着的副作用。目前尚不清楚为什么CML祖细胞在伊马替尼治疗的患者中存活，因此很难开发特定的方法来根除残留的白血病。该项目的长期目标是通过了解治疗期间CML祖细胞存活的机制来改善CML患者的预后和生活质量。我们有初步的数据证明CML祖细胞可以使用替代信号来补偿BCR-ABL激酶抑制剂治疗后BCR-ABL活性的丧失。此外，我们有证据表明，抑制干细胞因子受体KIT是伊马替尼对CML细胞作用的关键介质。最后，我们发现了一个基因 表达特征与伊马替尼的原发性细胞遗传学耐药相关，并且有证据表明betacatenin可能参与了特征基因的调节。我们提出三个具体目标： AIM 1.为了阐明BCR-ABL抑制后CML祖细胞存活的机制， 评估CML祖细胞是否依赖于BCR-ABL或JAK 2依赖性基质细胞衍生因子是否可以保护它们免受BCR-ABL抑制剂的影响。 AIM 2.为了确定KIT在抑制BCR-ABL后对CML祖细胞存活的作用，我们 将测试KIT的抑制是否是伊马替尼对CML祖细胞的生物学效应所必需的，以及KIT是否是BCR-ABL诱导CML所必需的。 AIM 3.确定β-连环蛋白在伊马替尼耐药中的作用。我们将确定betacatenin是否是与原发性伊马替尼失败相关的基因的主要调节因子，betacatenin acfivion是否赋予伊马替尼耐药性，以及betacatenin在CML祖细胞中如何调节。

Many patients with chronic myeloid leukemia (CML) attain excellent responses on imatinib (Gleevec). However, recurrence is the rule upon drug discontinuation, consistent with survival of fully leukemogenic CML progenitor cells in the presence of drug. Therefore, therapy must continue lifelong, often despite significant side effects. It is not well understood why CML progenitor cells survive in patients on imatinib, and therefore It is difficult to develop specific approaches to eradicate residual leukemia. The long-term objective of this project is to improve the prognosis and quality of life of CML patients, by understanding the mechanisms underlying the survival of CML progenitor cells during therapy. We have preliminary data suggesfing that CML progenitor cells can use alternative signals to compensate forthe loss of BCR-ABL acfivity upon treatment with BCR-ABL kinase inhibitors. Further we have evidence that inhibition ofthe stem cell factor recptor KIT Is a critical mediator of imatinib effcts on CML cells. Lastly, we have identified a gene expression signature associated with primary cytogenetic resistance to imatinib and have evidence that betacatenin may be involved in the regulation ofthe signature genes. We propose three Specific Aims: AIM 1. To elucidate mechanisms of CML progenitor cell survival upon inhibition of BCR-ABL .We will assess whether CML progenitor cells are dependent on BCR-ABL or whether JAK2-dependent stroma cellderived factors can protect them from the effects of BCR-ABL inhibitors. AIM 2. To determine the role of KIT for CML progenitor cell survival upon inhibition of BCR-ABL. We will test whether inhibifion of KIT is essential for the biological effects of imatinib on CML progenitor cells and whether KIT is required for BCR-ABL to induce CML. AIM 3. To determine the role of p-catenin for imatinib resistance. We will determine whether betacatenin is a master regulator of genes associated with primary imatinib failure, whether beta-catenin acfivafion confers imatinib resistance, and how beta-catenin is regulated in CML progenitor cells.