Identification of therapeutic targets for leukemia stem cells in AML-iPSC models
Identification of therapeutic targets for leukemia stem cells in AML-iPSC models
批准号:
10348154
负责人:
Michael Kharas
金额:
$65.22万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-03-01 至 2023-02-28
关键词:
ATAC-seqAcute Myelocytic LeukemiaAnthracyclineBiologicalBiological AssayBlood CellsBone MarrowCRISPR/Cas technologyCell CycleCell LineCell surfaceCellsChemoresistanceClonal EvolutionClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsCytarabineDifferentiation and GrowthEngineeringEngraftmentFLT3 geneFutureGenesGenotypeHematopoieticHematopoietic NeoplasmsHematopoietic stem cellsHeterogeneityHumanImmunodeficient MouseIn VitroInterphase CellKnock-outLaboratoriesLibrariesLymphocyteMaintenanceMegakaryocytesMethodologyMethodsModelingMolecularMolecular AnalysisMolecular ProfilingMusMutationMutation AnalysisMyeloproliferative diseasePathway interactionsPatientsPharmacologyPhenotypePopulationPropertyRecurrent diseaseRelapseResistanceSourceSuspensionsSystemTestingTimeTransplantationValidationXenograft procedureacute myeloid leukemia cellbasecancer cellchemotherapyconventional therapydrug developmentdrug discoverygenome editinggenome-widehematopoietic differentiationin vivoinduced pluripotent stem cellinsightknock-downleukemialeukemia relapseleukemic stem cellmouse modelnew therapeutic targetnoveloverexpressionpatient derived xenograft modelprospectiveresponsescreeningself-renewalsingle-cell RNA sequencingsmall hairpin RNAsmall moleculestem cell biologystem cell modelstem-like celltherapeutic target
中文摘要
项目总结/文摘
英文摘要
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.
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期刊论文(8)
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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.
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
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:
--
作者:
[Deslauriers AG, Kotini AG, Papapetrou EP]
通讯作者:
Papapetrou EP
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]
通讯作者:
Papapetrou,EiriniP
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资助金额:$40.5万
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