Determining the Microenvironmental Contribution to Acute Myeloid Leukemia Chemoresistance
确定微环境对急性髓系白血病化疗耐药性的影响
基本信息
- 批准号:10602784
- 负责人:
- 金额:$ 3.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcute Myelocytic LeukemiaAcute leukemiaAdultAntibodiesBiological AssayBiopsyBone MarrowBone Marrow AspirationBone Marrow CellsBone Marrow NeoplasmsBone marrow biopsyCRISPR/Cas technologyCXCR4 geneCell CommunicationCellsCellularityChemoresistanceChemosensitizationClinicalCoculture TechniquesComplementCytarabineCytotoxic ChemotherapyDetectionDiagnosisDiagnosticDiseaseEpitopesGeneticGenetic TranscriptionGoalsHematologic NeoplasmsHematopoiesisHematopoietic stem cellsHumanImageImmunologic Deficiency SyndromesImmunophenotypingIn SituKnock-outLeukemic CellLigandsMarrowMeasuresMediatingMediatorMembrane ProteinsMethodsMicroanatomyMorphologyMusMutationNPM1 genePatient SelectionPatientsPhysiologyPopulationPrognosisPrognostic FactorProliferation MarkerProteinsRelapseResidual NeoplasmResidual stateResistanceResolutionSamplingSourceStromal Cell-Derived Factor 1Stromal CellsSurvival RateSystemTimeTissuesVisualizationWorkacute myeloid leukemia cellc-myc Genescell typechemotherapyclinical remissionhematopoietic stem cell quiescencehuman tissueimprovedindexingleukemiamouse modelmultiplexed imagingmutantneoplastic cellnew therapeutic targetnovel therapeuticsoverexpressionpatient derived xenograft modelreceptorrelapse riskresponseself-renewalsingle-cell RNA sequencingstandard of carestem cell nichetargeted treatmenttherapy developmenttranscriptomicstreatment responsetumor
项目摘要
Acute Myeloid Leukemia (AML) is the most fatal hematologic malignancy in adults, largely due to high rates of
relapse following chemotherapy. Residual disease, the persistence of immunophenotypically, morphologically,
or genetically defined leukemia cells following frontline chemotherapy, is a poor prognostic factor for AML.
Residual AML cells have been shown to localize to endosteal bone marrow regions in murine models, where
they may utilize microanatomical niches specialized to support long-term quiescent hematopoietic stem cells to
become dormant and gain resistance to chemotherapy, which targets dividing cells. However, these niches are
ill-defined in human bone marrow, and it remains unclear whether human AML cells actually interact with
canonical stem cell niches as a mechanism to evade chemotherapy. Our central hypothesis is that AML cells
interact with cells in protective niches within bone marrow by overexpressing stem cell niche retention
receptors, which allows them to acquire chemoresistance. In Aim 1, we will employ Co-Indexing by Epitopes
(CODEX), a recently developed method to visualize dozens of antibody markers on a single-cell level from
fixed human tissue, to dissect the exact composition and spatial organization of human bone marrow niches.
For the first time, we will be able to determine where chemoresistant cells localize in clinical bone marrow
biopsies from AML patients. We will assess whether or not non-dividing residual AML cells localize
preferentially to endosteal stem cell niches in the bone marrow in response to chemotherapy. In Aim 2, we will
determine whether stem cell niche retention receptors are overexpressed on residual AML cells and promote
chemoresistance. To achieve this, in Aim 2A we will first perform single-cell RNA sequencing of AML bone
marrow aspirate samples from diagnosis and time of residual disease determination, as well as healthy
controls, providing an expression profile of AML cells, AML-associated microenvironmental cells, and their
healthy counterparts. We will determine whether receptors mediating niche retention are overexpressed. In
Aim 2B, we will assess whether they are functionally important for chemoresistance using CRISPR-Cas9
mediated knockout of overexpressed receptor-ligand pairs which mediate AML-stromal interaction in an AML-
stormal co-culture system that will be treated with cytotoxic chemotherapy. If AML cells indeed localize to these
endosteal niches and gain chemoresistance through receptor-ligand mediated interaction in the stem cell
niche, these receptor/ligand pairs would represent an attractive target for chemosensitization, which may help
reduce AML relapse risk. Together, this project is poised to evaluate whether leukemic cells hijack healthy
stem cell niches to evade standard-of-care chemotherapy, and this work has the potential to reveal new
therapeutic opportunities to better treat this deadly disease.
急性髓系白血病(AML)是成人中最致命的血液恶性肿瘤,主要是由于高发病率,
化疗后复发。残留疾病,免疫表型,形态学,
或遗传定义的白血病细胞后一线化疗,是一个不良的预后因素AML。
在小鼠模型中,残留的AML细胞已显示定位于骨内膜骨髓区域,其中
它们可以利用专门支持长期静止的造血干细胞的微解剖学小生境,
进入休眠状态并对针对分裂细胞的化疗产生抵抗力。然而,这些壁龛是
在人类骨髓中定义不清,目前还不清楚人类AML细胞是否真的与
典型的干细胞壁龛作为逃避化疗的机制。我们的核心假设是AML细胞
通过过表达干细胞龛保持与骨髓内保护龛中的细胞相互作用
受体,这使他们能够获得耐药性。在目标1中,我们将采用表位共索引
(CODEX),最近开发的一种在单细胞水平上可视化数十种抗体标记物的方法,
固定的人体组织,解剖人体骨髓龛的确切组成和空间组织。
这是第一次,我们将能够确定耐药细胞在临床骨髓中的定位
AML患者的活检。我们将评估未分裂的残余AML细胞是否定位于
优先于骨髓中的骨内膜干细胞小生境,以响应化疗。在目标2中,我们将
确定干细胞生态位保留受体是否在残留的AML细胞上过表达,并促进
化学抗性为了实现这一目标,在Aim 2A中,我们将首先对AML骨进行单细胞RNA测序,
来自诊断和残留疾病确定时间的骨髓穿刺样品,以及健康人
对照,提供AML细胞、AML相关的微环境细胞和它们的表达谱。
健康的同行我们将确定是否受体介导的利基保留过表达。在
目的2B,我们将使用CRISPR-Cas9评估它们是否对化学抗性具有功能重要性。
介导的敲除过表达的受体-配体对,所述受体-配体对介导AML-基质相互作用,
风暴共培养系统,将与细胞毒性化疗治疗。如果AML细胞确实定位于这些
通过干细胞中受体-配体介导的相互作用,
利基,这些受体/配体对将代表一个有吸引力的目标化疗增敏,这可能有助于
降低AML复发风险。总之,这个项目准备评估白血病细胞是否劫持健康的
干细胞龛逃避标准治疗化疗,这项工作有可能揭示新的
更好地治疗这种致命疾病的治疗机会。
项目成果
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