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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

基本信息

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
项目类别：
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

项目摘要

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. !

项目总结/文摘

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.
通讯作者：
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.)
影响因子：
0
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。