Identification of therapeutic targets for leukemia stem cells in AML-iPSC models

项目总结/摘要 急性髓系白血病（AML）是一种高度侵袭性的血液癌症，中位总生存期约为1年。 虽然大多数患者最初对化疗有反应，但许多患者随后复发。的 AML中的恶性细胞显示出分层组织，白血病干细胞（LSC）位于顶端。 LSC被认为是化疗耐药性和AML复发的主要来源，因为它们具有 与大多数AML人群相比，AML具有独特的生物学特性，因此可能对大多数AML耐药。 传统疗法。因此，专门针对LSC的疗法理论上可以提供更持久的治疗效果。 反应，甚至治愈。尽管有大量证据表明， LSC，其研究存在重大挑战。LSC目前由其功能特性定义， 小鼠或异种移植模型。它们与正常造血干细胞（HSC）的相似性， 以及缺乏区分LSC和其他AML细胞的特异性免疫表型标记 使得它们在药物发现中的预期分离、研究和使用具有挑战性。 我们（Papapetrou实验室）已经率先用诱导多能造血干细胞模型建立了骨髓恶性肿瘤模型。 干细胞（iPSC）。我们最近获得了AML的第一个iPSC模型（AML-iPSC）。的密切协作下 在Kharas实验室，我们发现来自AML的造血干/祖细胞（HSPCs）- iPSC概括了LSC的显著特征，例如高增殖潜能、多潜能性、连续性、多细胞性、多细胞性和多细胞性。 在免疫缺陷小鼠中移植致死性白血病和等级组织， 表型和功能异质性。因此，AML-iPSC模型首次使全基因组 在相关LSC样细胞中进行整合分子分析、大规模筛选以及体外和体内验证， 人体细胞在本申请中，我们将使用这些非常新颖的AML-iPSC模型来鉴定关键分子， 维持LSC特性的机制可能构成有前途的治疗靶点。拟议 研究利用了Papapetrou实验室在iPSC建模方面的独特专业知识， Kharas实验室在研究骨髓恶性肿瘤的分子机制，并可以产生新的见解， LSC生物学和确定未来药物开发的新治疗靶点。 !

PROJECT SUMMARY/ABSTRACT Acute Myeloid Leukemia (AML) is a highly aggressive blood cancer with median overall survival of ~1 year. Although most patients respond to treatment with chemotherapy initially, many subsequently relapse. The malignant cells in AML display a hierarchical organization with leukemia stem cells (LSCs) residing in the apex. LSCs are believed to be a prominent source of chemotherapy resistance and AML relapse, because they have distinct biological properties than the bulk AML population and are therefore presumably resistant to most conventional therapies. Thus therapies specifically targeting LSCs could theoretically give more lasting responses or even cures. Although there is substantial evidence for the existence of both murine and human LSCs, significant challenges to their study exist. LSCs are currently defined by their functional properties in mouse or xenotransplantation models. Their similarities to normal hematopoietic stem cells (HSCs), their rarity and the unavailability of specific immunophenotypic markers that distinguish LSCs from the rest of AML cells makes their prospective isolation, study and use in drug discovery challenging. We (Papapetrou laboratory) have pioneered the modeling of myeloid malignancies with induced pluripotent stem cells (iPSCs). We recently derived the first iPSC models of AML (AML-iPSCs). In close collaboration with the Kharas laboratory, we found that the hematopoietic stem/progenitor cells (HSPCs) derived from AML- iPSCs recapitulate salient features of LSCs, such as high proliferation potential, multipotentiality, serial engraftment of a lethal leukemia in immunodeficient mice and hierarchical organization giving rise to phenotypic and functional heterogeneity. Thus AML-iPSC models enable for the first time genome-wide integrative molecular analyses, large-scale screening and in vitro and in vivo validation in relevant LSC-like human cells. In this application we will use these very novel AML-iPSC models to identify key molecular mechanisms sustaining LSC properties that may constitute promising therapeutic targets. The proposed studies leverage the unique expertise of the Papapetrou lab in iPSC modeling, combined with the expertise of the Kharas lab in studying molecular mechanisms of myeloid malignancy and can generate new insights into LSC biology and identify new therapeutic targets for future drug development. !