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

AML-iPSC 模型中白血病干细胞治疗靶点的鉴定

• 批准号: 10348154
• 负责人: Michael Kharas
• 金额: $ 65.22万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348154
• 关键词: ATAC-seq; Acute Myelocytic Leukemia; Anthracycline; Biological; Biological Assay; Blood Cells; Bone Marrow; CRISPR/Cas technology; Cell Cycle; Cell Line; Cell surface; Cells; Chemoresistance; Clonal Evolution; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Cytarabine; Differentiation and Growth; Engineering; Engraftment; FLT3 gene; Future; Genes; Genotype; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heterogeneity; Human; Immunodeficient Mouse; In Vitro; Interphase Cell; Knock-out; Laboratories; Libraries; Lymphocyte; Maintenance; Megakaryocytes; Methodology; Methods; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Mus; Mutation; Mutation Analysis; Myeloproliferative disease; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Property; Recurrent disease; Relapse; Resistance; Source; Suspensions; System; Testing; Time; Transplantation; Validation; Xenograft procedure; acute myeloid leukemia cell; base; cancer cell; chemotherapy; conventional therapy; drug development; drug discovery; genome editing; genome-wide; hematopoietic differentiation; in vivo; induced pluripotent stem cell; insight; knock-down; leukemia; leukemia relapse; leukemic stem cell; mouse model; new therapeutic target; novel; overexpression; patient derived xenograft model; prospective; response; screening; self-renewal; single-cell RNA sequencing; small hairpin RNA; small molecule; stem cell biology; stem cell model; stem-like cell; therapeutic target

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. !

项目摘要/摘要 急性髓系白血病(AML)是一种高度侵袭性的血癌，中位总生存期为1年。 虽然大多数患者最初对化疗有反应，但许多人后来复发。这个 AML中的恶性细胞呈层次化组织，白血病干细胞(LSCs)位于顶端。 LSCs被认为是化疗耐药和AML复发的重要来源，因为它们有 与大量AML人群不同的生物学特性，因此可能对大多数 传统疗法。因此，从理论上讲，针对LSCs的治疗方法可以提供更持久的 反应，甚至治愈。尽管有大量证据表明老鼠和人类都存在 LSC，他们的研究面临着重大挑战。LSC当前由中的功能属性定义 小鼠或异种移植模型。它们与正常造血干细胞(HSCs)的相似性，它们的稀有性 以及无法获得区分LSCs和其他AML细胞的特定免疫表型标记 这使得它们未来的分离、研究和在药物发现中的使用具有挑战性。 我们(Papapetrou实验室)率先用诱导多能技术建立了髓系恶性肿瘤的模型 干细胞(IPSCs)。我们最近推出了AML的第一个IPSC模型(AML-IPSCs)。与……密切合作 在Kharas实验室，我们发现AML来源的造血干/祖细胞(HSPC)- IPSCs概括了LSCs的显著特征，如高增殖潜能、多潜能、系列化 致死性白血病在免疫缺陷小鼠体内的植入和层级组织 表型和功能的异质性。因此，AML-IPSC模型首次实现了全基因组 相关LSC样蛋白的分子综合分析、大规模筛选和体内外验证 人类细胞。在这个应用中，我们将使用这些非常新颖的AML-IPSC模型来识别关键分子 维持LSC特性的机制可能成为有希望的治疗靶点。建议数 研究利用Papapetrou实验室在IPSC建模方面的独特专业知识，结合 哈拉斯实验室研究髓系恶性肿瘤的分子机制并可以产生新的见解 LSC生物学，并为未来的药物开发确定新的治疗靶点。 好了！

项目成果

MDS/AML with del5q: An acquired "laminopathy"?

• DOI: 10.1016/j.stem.2022.03.008
• 发表时间: 2022-04-07
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Papapetrou, Eirini P.

Studying leukemia stem cell properties and vulnerabilities with human iPSCs.

• DOI: 10.1016/j.scr.2020.102117
• 发表时间: 2020-12-10
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: Spyrou N;Papapetrou EP
• 通讯作者: Papapetrou EP

Modeling Leukemia Stem Cells with Patient-Derived Induced Pluripotent Stem Cells.

• DOI: 10.1007/978-1-0716-0810-4_26
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Deslauriers AG;Kotini AG;Papapetrou EP
• 通讯作者: Papapetrou EP

Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs.

• DOI: 10.1182/bloodadvances.2021006325
• 发表时间: 2022-05-24
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Asimomitis, Georgios;G. Deslaurnes, Andre;Kotini, Andriana G.;Bernard, Elsa;Esposito, Davide;Olszewska, Malgorzata;Spyrou, Nikolaos;Ossa, Juan Arango;Mortera-Blanco, Teresa;Koche, Richard;Malcovati, Luca;Ogawa, Seishi;Cazzola, Mario;Aaronson, Stuart A.;Hellstro-Lindberg, Eva;Papaemmanuil, Elli;Nannya, Yasuhito;Papapetrou, Eirini P.
• 通讯作者: Papapetrou, Eirini P.

Modeling Leukemia with Human Induced Pluripotent Stem Cells.

用人类诱导多能干细胞模拟白血病。

• DOI: 10.1101/cshperspect.a034868
• 发表时间: 2019
• 期刊: Cold Spring Harbor perspectives in medicine
• 影响因子: 5.4
• 作者: Papapetrou,EiriniP