Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
批准号:
10394937
负责人:
Warren D Shlomchik
金额:
$59.7万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-04-20 至 2025-03-31
关键词:
Acute Lymphocytic LeukemiaAcute Myelocytic LeukemiaAddressAffinityAlloantigenAllogenicAllograftingBiological ModelsBiologyBlast PhaseBone Marrow CellsCD8B1 geneCRISPR/Cas technologyCSPG6 geneCause of DeathCellsChronic-Phase Myeloid LeukemiaClinicClinicalClinical DataClustered Regularly Interspaced Short Palindromic RepeatsCytomegalovirusDataDonor personFLT3 geneFailureFutureGene DeletionGene ExpressionGenesGeneticHOXA9 geneHematologic NeoplasmsHematopoietic NeoplasmsHematopoietic Stem Cell TransplantationHematopoietic stem cellsHeterogeneityHumanIFNGR1 geneImmuneIntercellular adhesion molecule 1Interferon Type IIInterferonsKRAS2 geneKnock-inKnock-outKnockout MiceKnowledgeLeadLeukemic CellMLL-AF9MediatingMinor Histocompatibility AntigensModelingMolecular AbnormalityMusNUP98 geneNatural Killer CellsNeoplasmsOncogenesPatientsPersonsPhenocopyPropertyRecurrent diseaseRelapseResistanceRoleSTAT1 geneSTAT2 geneSpecimenStem cell transplantT cell responseT cell therapyT-LymphocyteTP53 geneTestingTransplantationWorkacute myeloid leukemia cellcell killingcellular transductionclinical applicationcurative treatmentsexperimental studygraft vs host diseasegraft vs leukemia effectleukemialeukemia relapseminor H antigen H60molecular subtypesmouse modeloverexpressionpleiotropismpost-transplantsingle-cell RNA sequencingstem cellstherapeutic targettool
中文摘要
抽象的。
异基因造血干细胞移植是一种最常用的根治疗法。
急性髓细胞白血病(AML)的治疗。同种异体抗体T细胞的子代
同种异体移植物可以杀伤受体白血病细胞,从而介导移植物抗白血病效应(GVL)。不过,
疾病复发,表明GVL不足,是移植后最常见的死亡原因。
尽管所有类型的白血病都表达同种异体抗原,但GVL耐药性和敏感性在不同类别的白血病中并不相等。
例如,慢性期慢性粒细胞白血病(CP-CML)对GVL非常敏感,而
尽管具有共同的生物学特性,但BCML(BC-CML)对GVL具有抗性。同样,急性髓系白血病和急性白血病
淋巴细胞性白血病相对耐GVL。因为GVL-电阻和-灵敏度与
肿瘤的分类,我们推断它们是白血病细胞的固有属性。因此,我们成立了GVL
对抗MCP-CML和MBC-CML的小鼠模型,这些模型是用真正的人类癌基因创造的。通过
基因缺陷性白血病的建立我们发现,为了有效的GVL,MBCML需要干扰素-γR
而GVL对STAT1/STAT2-/-MCP-CML是完全完整的,不能对任何类型的
干扰素。干扰素-γR-/-MLL-AF9对GVL也具有抗性。这些数据表明,有效的GVL抗成髓细胞
白血病需要高强度的同种异体反应性T细胞反应来产生干扰素-g,而更多的
阴燃的T细胞反应不会产生太多的干扰素-g,但可以有效地对抗CP-CML。这些结果
也强烈表明,干扰素-g的交付,与同种异体反应性或白血病反应性T细胞,
会产生重大的临床影响。然而,需要回答关键问题才能最佳地应用干扰素-g或
在临床上诱导其某些影响的药物。首先,虽然所有AML亚型都有一些共同的生物学特征,
司机的基因有很大的异质性。因此,了解哪些AML是至关重要的
分子亚型需要干扰素-g才能获得最佳的GVL。我们的目标是通过使用CRISPR-Cas9来删除干扰素-
在表达关键γ驱动因素的复合基因编辑小鼠中发生的可移植白血病的AMLR
基因,有时伴随着基因缺失。我们已经成功地编辑了干扰素-γR
JAK2V617F/P53-/-和Flt3-ITD/DNMT3-/-/NPM1c AML。其次,干扰素-g是一种钝化的工具,具有多效性。
这可能会促进移植物抗宿主疾病。因此,我们的目标是了解在什么情况下同种异体免疫
干扰素-g是必需的,以及哪些特定的下游效应是使AML细胞对GVL敏感的关键。我们有
已开发的恢复干扰素-g诱导的关键基因表达的方法(例如,CIITA、NLRC5、ICAM-1)
与干扰素-γR-/-白血病有关,以便具体询问它们的相关性。将会发现更多的目标
通过单细胞RNAseq,重点研究干扰素-g诱导的干细胞亚群基因表达的变化
细胞质量。然后这些靶标可以在干扰素-γ-R白血病中被删除或表达,以进一步定义它们的
重要性。
英文摘要
Abstract.
Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative therapy most commonly applied in
treatment of patients with acute myeloblastic leukemia (AML). The progeny of alloreactive ab T cells in the
allograft can kill recipient leukemia cells, thereby mediating the graft-vs-leukemia effect (GVL). Nevertheless,
disease relapse, indicative of insufficient GVL, is the single most common cause of death post-transplant.
GVL-resistance and sensitivity are not equal across classes of leukemias, despite all expressing alloantigens.
For example, chronic phase chronic myelogenous leukemia (CP-CML) is exquisitely GVL-sensitive whereas
blast crisis CML (BC-CML) is GVL-resistant, despite sharing common biology. Likewise, AML and acute
lymphoblastic leukemia are relatively GVL-resistant. Because GVL-resistance and -sensitivity track with the
class of neoplasm, we reasoned that they are leukemia cell-intrinsic properties. We therefore established GVL
against mouse models of mCP-CML and mBC-CML created with authentic human oncogenes. Through the
creation of gene-deficient leukemias we discovered that for effective GVL, mBC-CML requires IFN-γR
stimulation whereas GVL is fully intact against STAT1/STAT2-/- mCP-CML that cannot respond to any type of
IFN. IFN-γR-/- MLL-AF9 was also GVL-resistant. These data indicate that effective GVL against myeloblastic
leukemias requires a high magnitude alloreactive T cell response that generates IFN-g whereas a more
smoldering T cell response that does not create much IFN-g can be effective against CP-CML. These results
also strongly suggest that the delivery of IFN-g, in conjunction with alloreactive or leukemia-reactive T cells,
would have a major clinical impact. However, key questions need to be answered to optimally apply IFN-g or
agents that induce some of its effects in the clinic. First, while all AML subtypes share some common biology,
there is substantial heterogeneity in driver genes. It will therefore be critical to understand which AML
molecular subtypes require IFN-g for optimal GVL. We aim to do so by using CRISPR-Cas9 to delete the IFN-
γR from transplantable leukemias that develop in compound gene-edited mice that express key AML-driver
genes, sometimes in conjunction with a gene deletion. We have already successfully edited the IFN-γR from
JAK2V617F/p53-/- and FLT3-ITD/DNMT3-/-/NPM1c AMLs. Second, IFN-g is a blunt tool with pleiotropic effects
that could promote graft-vs-host disease. Therefore, we aim to understand under what alloimmune conditions
IFN-g is required and what specific downstream effects are essential to sensitize AML cells to GVL. We have
already developed approaches to restore expression of key IFN-g-induced genes (e.g. CIITA, NLRC5, ICAM-1)
to IFN-γR-/- leukemias in order to specifically interrogate their relevance. Further targets will be discovered
through single cell RNAseq, focusing on IFN-g-induced gene expression changes in subpopulations with stem
cell qualities. These targets could then be deleted or expressed in IFN-γR leukemias to further define their
importance.
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会议论文
Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
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批准号:10609407
-
项目类别:
-
资助金额:$60.46万
-
财政年份:2021
-
负责人:Warren D Shlomchik
-
依托单位:
Mechanisms whereby IFN-gamma sensitizes AML to the graft-vs-leukemia effect
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批准号:10217590
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项目类别:
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资助金额:$58.51万
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财政年份:2021
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负责人:Warren D Shlomchik
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依托单位:
Graft-versus-Host Disease: Local Maintenance in Target Tissues by Tissue Resident Memory-Type Cells.
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批准号:9756456
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项目类别:
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资助金额:$65.56万
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财政年份:2018
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负责人:Warren D Shlomchik
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依托单位:
Graft-versus-Host Disease: Local Maintenance in Target Tissues by Tissue Resident Memory-Type Cells.
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批准号:10165801
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项目类别:
-
资助金额:$63.26万
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财政年份:2018
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负责人:Warren D Shlomchik
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依托单位:
GVL Resistance: Immune selection, T cell ignorance and T cell exhaustion
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批准号:8675278
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项目类别:
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资助金额:$40.79万
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财政年份:2013
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负责人:Warren D Shlomchik
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依托单位:
GVL Resistance: Immune selection, T cell ignorance and T cell exhaustion
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批准号:8477401
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项目类别:
-
资助金额:$39.62万
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财政年份:2013
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负责人:Warren D Shlomchik
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依托单位:
GVL Resistance: Immune selection, T cell ignorance and T cell exhaustion
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批准号:9039753
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项目类别:
-
资助金额:$37.92万
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财政年份:2013
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负责人:Warren D Shlomchik
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依托单位:
Dendritic Cell Subsets and Paths of Maturation in GVHD
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批准号:8117703
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项目类别:
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资助金额:$48.98万
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财政年份:2010
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负责人:Warren D Shlomchik
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依托单位:
Research Core (Amnis ImageStreamX Core)
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批准号:8725465
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项目类别:
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资助金额:$15.72万
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财政年份:2007
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负责人:Warren D Shlomchik
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依托单位:
Research Core (Amnis ImageStreamX Core)
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批准号:8444012
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项目类别:
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资助金额:$9.97万
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财政年份:2007
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负责人:Warren D Shlomchik
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依托单位:
Research Core (Amnis ImageStreamX Core)
-
批准号:8900948
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项目类别:
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资助金额:$15.61万
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财政年份:2007
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负责人:Warren D Shlomchik
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依托单位:
Research Core (Amnis ImageStreamX Core)
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批准号:9543603
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项目类别:
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资助金额:$16.75万
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财政年份:2007
-
负责人:Warren D Shlomchik
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依托单位:
Research Core (Amnis ImageStreamX Core)
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批准号:8534032
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项目类别:
-
资助金额:$15.4万
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财政年份:2007
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负责人:Warren D Shlomchik
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依托单位:
Dendritic Cell Subsets and Paths of Maturation in GVHD
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批准号:7136041
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项目类别:
-
资助金额:$30.29万
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财政年份:2006
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负责人:Warren D Shlomchik
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依托单位:
Role of Tissue Antigen Presenting Cells in GVHD
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批准号:8680312
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项目类别:
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资助金额:$40.79万
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财政年份:2006
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负责人:Warren D Shlomchik
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依托单位:
Role of Tissue Antigen Presenting Cells in GVHD
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批准号:8293033
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项目类别:
-
资助金额:$41.5万
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财政年份:2006
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负责人:Warren D Shlomchik
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依托单位:
Dendritic Cell Subsets and Paths of Maturation in Graft-vs.-Host Disease (GVHD)
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批准号:7265207
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项目类别:
-
资助金额:$16.5万
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财政年份:2006
-
负责人:Warren D Shlomchik
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依托单位:
Dendritic Cell Subsets and Paths of Maturation in Graft-vs.-Host Disease (GVHD)
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批准号:7465557
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项目类别:
-
资助金额:$16.55万
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财政年份:2006
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负责人:Warren D Shlomchik
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依托单位:
Dendritic Cell Subsets and Paths of Maturation in Graft-vs.-Host Disease (GVHD)
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批准号:7881498
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项目类别:
-
资助金额:$16.55万
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财政年份:2006
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负责人:Warren D Shlomchik
-
依托单位:
Dendritic Cell Subsets and Paths of Maturation in GVHD
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批准号:7147377
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项目类别:
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资助金额:$20.63万
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财政年份:2006
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负责人:Warren D Shlomchik
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依托单位:
海外基金