A role for elevated autophagy in survival and chemoresistance of leukemia stem ce

描述(申请人提供)：急性髓系白血病(AML)是一种致命的疾病，大多数患者在获得初步完全缓解(CR)后仍会死亡。即使在非常激进的多药化疗方案和清髓性异基因干细胞移植的情况下，复发率也很高。因此，了解导致复发的机制至关重要。越来越多的证据表明，AML是由白血病干细胞(LSCs)亚群产生和维持的，LSCs对标准化疗具有抵抗力，从而提供了推动疾病复发的细胞库。LSCs处于一种不同于正常同龄人的独特的生理状态，并且已经对NFkappaB等通路上瘾以求生存。我们最近发现，LSC表现出自噬增加，因此假设自噬是LSC存活和化疗耐药的中介。我们提出了以下具体目标：(1)检验自噬机制在LSC中上调的假设，赋予LSC生存优势和化疗耐药特性；(2)检验自噬途径的化学或遗传扰动将降低LSC存活和化疗耐药的假说；(3)确定已知的抗LSC药物抑制自噬过程的能力。评估自噬作为LSC化疗耐药和复发的中介对于更好地描述LSC的独特特征至关重要，这些特征可以用于改善AML的治疗。这项建议将解决自噬是否代表一个可行的治疗靶点和/或使LSCs对诱导治疗敏感，从而减少复发的可能性。 公共卫生相关性：急性髓系白血病(AML)是一种致命的疾病，对大多数患者来说复发率很高，迫切需要新的治疗策略。AML复发被认为是由化疗耐药的白血病干细胞(LSCs)引起的。这项建议旨在确定自噬水平的增加是否有助于LSC的存活和化疗耐药，从而代表了改善LSC根除的目标。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a fatal disease in which most patients die despite achieving initial complete remission (CR). Even under very aggressive multi-agent chemotherapy regimens and myeloablative allogeneic stem cell transplantation, relapse rates are high. Thus, understanding the mechanisms that lead to relapse is critical. Increasing evidence suggests that AML is originated and maintained by a subpopulation of leukemic stem cells (LSCs), which are resistant to standard chemotherapy and thereby provide a reservoir of cells that drive disease relapse. LSCs reside in a unique physiologic state from their normal counterparts and have acquired addiction to pathways such as NFkappaB for survival. We have recently discovered that LSCs demonstrate increased autophagy and thus hypothesize that autophagy is a mediator of LSC survival and chemoresistance. We propose the following specific aims: (1) to test the hypothesis that autophagy mechanisms are upregulated in LSCs when compared to their normal counterparts, conferring survival advantages and chemoresistance properties on LSCs; (2) to test the hypothesis chemical or genetic perturbation of the autophagy pathways will decrease LSC survival and chemoresistance; (3) to determine the ability of known anti-LSC drugs to inhibit the autophagy process. The evaluation of autophagy as a mediator of LSC chemoresistance and relapse is critical towards better delineating the unique features of LSCs that can be capitalized upon towards improving AML therapy. This proposal will address whether autophagy represents a feasible therapeutic target and/or sensitizes LSCs to induction therapy, diminishing the likelihood of relapse. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia (AML) is a fatal disease with high incidence of relapse for most patients and novel treatment strategies are urgently needed. AML relapse is thought to arise from chemoresistant leukemia stem cells (LSCs). This proposal aims to determine whether increased levels of autophagy in LSCs contribute to their survival and chemoresistance, thereby representing a target to improve LSC eradication.