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

描述（由申请人提供）：急性髓性白血病（AML）是一种致死性疾病，大多数患者即使达到初始完全缓解（CR）也会死亡。即使在非常积极的多药化疗方案和清髓性异基因干细胞移植，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（LSC）亚群起源和维持的，这些细胞对标准化疗具有抗性，从而提供了一个驱动疾病复发的细胞库。LSC与其正常对应物相比处于独特的生理状态，并且已经获得对诸如NF κ B的通路的成瘾以存活。我们最近发现LSC表现出增加的自噬，因此假设自噬是LSC存活和化疗抗性的介导者。我们提出了以下具体目标：（1）检验自噬机制在LSC中与其正常对应物相比上调的假设，赋予LSC生存优势和化学抗性特性;（2）检验自噬途径的化学或遗传扰动将降低LSC存活和化学抗性的假设;（3）确定已知的抗LSC药物抑制自噬过程的能力。自噬作为LSC化疗耐药性和复发的介导物的评价对于更好地描述LSC的独特特征至关重要，这些特征可以用于改善AML治疗。该提案将解决自噬是否代表可行的治疗靶点和/或使LSC对诱导治疗敏感，从而降低复发的可能性。

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.