Differentiation-focused CRISPR Screen identifies LSD1 and Menin as combination therapy targets that induce terminal differentiation in AML
以分化为重点的 CRISPR 筛选将 LSD1 和 Menin 确定为诱导 AML 终末分化的联合治疗靶点
基本信息
- 批准号:10678478
- 负责人:
- 金额:$ 4.77万
- 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:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcute Myelocytic LeukemiaAdoptedAutomobile DrivingBiological AssayBloodCD86 geneCRISPR screenCRISPR/Cas technologyCell CycleCell Differentiation processCell modelCellsCellular AssayCessation of lifeChIP-seqCharacteristicsChromatinClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombinatoricsCombined Modality TherapyDataDifferentiated GeneDifferentiation TherapyDiseaseDisease remissionEpigenetic ProcessExperimental ModelsGenesGenomicsHematopoietic NeoplasmsHumanHuman Cell LineITGAM geneIndividualKDM1A geneLibrariesMLL-rearranged leukemiaMalignant NeoplasmsMeninMethodologyMethodsModelingMolecularMusMyelogenousOncogenesPathway interactionsPatientsPharmacologic SubstancePhenotypePrognosisProgranulocytesProliferatingProteinsRegulationRelapseReportingRepressionRestRoleSamplingSurfaceTestingTherapeuticTranscription CoactivatorTranscription RepressorTreatment EfficacyXenograft Modelacute myeloid leukemia cellchemotherapycofactorcohortcombinatorialcytotoxicityderepressiondifferential expressionepigenomicsexperimental studygene repressionhistological stainshistone demethylaseimprovedin vivoinhibitorinterestleukemiamouse modelnovelpharmacologicpreclinical efficacypreventprogenitorprogramsself-renewalsmall moleculesmall molecule inhibitorstandard of carestemstemnesssynergismtargeted treatmenttherapeutic evaluationtranscription factortranscriptome sequencingtranscriptomicstransplant modeltreatment strategy
项目摘要
Project Summary
Acute myeloid leukemia (AML) is a lethal blood cancer characterized by a differentiation “block” that prevents
myeloid progenitor maturation resulting in uncontrolled proliferation. Chemotherapy, the current standard of care,
is often ineffective and can result in cytotoxicity and relapse. New treatment options are desperately needed to
treat AML’s poor prognosis. Differentiation therapy is a novel method that aims to reactivate latent maturation
programs and induce cell cycle exit. This therapeutic strategy is curative in the promyelocytic (APL) AML subtype
but underexplored in other AMLs. Epigenetic factors help sustain the characteristic AML differentiation block.
The demethylase LSD1 has emerged as a promising target for differentiation therapy. Pharmacologic inhibition
of LSD1 (LSD1i) induces cellular differentiation in many AML subtypes. However, the extent of differentiation
varies between AML models, with a modest effect in aggressive AML models. Therefore, LSD1i will not induce
terminal differentiation as a monoagent treatment. We hypothesized that targeting additional epigenetic
regulators simultaneously with LSD1i may induce complete, terminal differentiation and lead to disease
remission. To identify potentiators of LSD1i, we conducted CRISPR gain-of-differentiation screens with a
chromatin-focused sgRNA library in multiple AML cell models with or without LSD1i co-treatment. These screens
unveiled a synergistic induction of differentiation when KO of MEN1 is combined with LSD1i. I confirmed that
combinatorial small molecule inhibition of LSD1 and MEN1 induces differentiation and reduces proliferation most
commonly in MLL-rearranged AMLs, and to a lesser extent in selected MLL-wild type AMLs. This proposal has
two aims: First, I will test the therapeutic potential of targeting MEN1 in combination with LSD1 inhibitors in
primary patient samples ex vivo and in patient-derived AML transplant models. Patient samples will be treated
with a MEN1 inhibitor in combination with LSD1 inhibitors, and effects on differentiation and proliferation will be
quantified. Secondly, I will determine the epigenomic mechanisms by which MEN1 and LSD1 inhibition synergize
to induce terminal differentiation, and then test whether these mechanisms are conserved in primary patient
samples.
项目概要
急性髓系白血病 (AML) 是一种致命的血液癌症,其特征是分化“阻断”,可阻止
骨髓祖细胞成熟导致不受控制的增殖。化疗,当前的护理标准,
通常无效,并可能导致细胞毒性和复发。迫切需要新的治疗方案
治疗 AML 的不良预后。分化疗法是一种旨在重新激活潜在成熟的新方法
程序并诱导细胞周期退出。这种治疗策略对早幼粒细胞 (APL) AML 亚型有疗效
但在其他反洗钱中尚未得到充分探索。表观遗传因素有助于维持特有的 AML 分化障碍。
去甲基化酶 LSD1 已成为分化治疗的一个有前景的靶标。药理抑制
LSD1 (LSD1i) 可诱导许多 AML 亚型的细胞分化。但分化程度
不同 AML 模型之间存在差异,在侵袭性 AML 模型中影响不大。因此,LSD1i 不会诱导
作为单一药物治疗的终末分化。我们假设针对额外的表观遗传
与 LSD1i 同时存在的调节因子可能诱导完全的终末分化并导致疾病
缓解。为了鉴定 LSD1i 的增强剂,我们进行了 CRISPR 分化增益筛选
在有或没有 LSD1i 联合治疗的多个 AML 细胞模型中以染色质为中心的 sgRNA 文库。这些屏幕
揭示了当 MEN1 的 KO 与 LSD1i 组合时协同诱导分化。我确认了
LSD1 和 MEN1 的组合小分子抑制最能诱导分化并减少增殖
常见于 MLL 重排 AML,并且较小程度地存在于选定的 MLL 野生型 AML。该提案有
有两个目标:首先,我将测试针对 MEN1 与 LSD1 抑制剂联合治疗的治疗潜力
体外和患者来源的 AML 移植模型中的主要患者样本。患者样本将被处理
MEN1 抑制剂与 LSD1 抑制剂联合使用,对分化和增殖的影响将
量化。其次,我将确定 MEN1 和 LSD1 抑制协同作用的表观基因组机制
诱导终末分化,然后测试这些机制在原发患者中是否保守
样品。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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