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

自噬升高在白血病干细胞存活和化疗耐药中的作用

• 批准号: 8244092
• 负责人: Monica L Guzman
• 金额: $ 22.05万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244092
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; Allogenic; Autophagocytosis; Biological; Blast Cell; Blood Cells; Cell Survival; Cells; Characteristics; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Data; Diagnosis; Disease; Disease Outcome; Disease remission; Drug resistance; Evaluation; Failure; Genetic; Goals; Hematopoietic; Hematopoietic stem cells; Incidence; Lead; Malignant - descriptor; Mediator of activation protein; Myeloablative Chemotherapy; Neoadjuvant Therapy; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Physiological; Physiological Processes; Play; Population; Process; Property; Recurrent disease; Regimen; Relapse; Relative (related person); Resistance; Role; Stem cell transplant; System; Testing; Therapeutic; Toxic effect; addiction; chemotherapeutic agent; chemotherapy; design; improved; inhibition of autophagy; inhibitor/antagonist; innovation; leukemia; leukemic stem cell; novel; small molecule; stem; stem cell biology; success; therapeutic target; transcription factor; treatment strategy

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.

描述（由申请人提供）：急性髓细胞性白血病（AML）是一种致命疾病，尽管大多数患者达到了最初的完全缓解（CR），但大多数患者死亡。即使在非常侵略性的多项式化疗方案和髓质同种异体干细胞移植中，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是由白血病细胞（LSC）的亚群来起源和维持的，这些细胞（LSC）对标准化学疗法有抵抗力，从而提供了驱动疾病复发的细胞储层。 LSC居住在其正常对应物中的独特生理状态，并已将成瘾成瘾（例如NFKappab）以生存。我们最近发现，LSC表现出自噬的增加，因此假设自噬是LSC生存和化学抗性的中介。我们提出以下特定目的：（1）检验以下假设：与正常对应物相比，LSC中自噬机制在LSC中上调，从而赋予了LSC上的生存优势和化学能力； （2）测试自噬途径的假设化学或遗传扰动将降低LSC的存活率和化学抗性； （3）确定已知抗LSC药物抑制自噬过程的能力。评估自噬作为LSC化学耐药和复发的介体，对于更好地描述LSC的独特特征至关重要，这些特征可用于改善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对诱导疗法的敏感，从而减少了复发的可能性。 公共卫生相关性：急性髓样白血病（AML）是一种致命疾病，大多数患者的复发发生率很高，并且迫切需要新颖的治疗策略。 AML复发被认为是由化学抗性白血病干细胞（LSC）引起的。该建议旨在确定LSC中自噬水平的增加是否有助于其生存和化学抗性，从而代表改善LSC消除的靶标。