CD25-mediated feedback control of BCR-signaling and its oncogenic mimics
CD25 介导的 BCR 信号反馈控制及其致癌模拟物
基本信息
- 批准号:10455511
- 负责人:
- 金额:$ 16.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:ABL1 geneAblationAcute Lymphocytic LeukemiaAdjuvantAdjuvant ChemotherapyAntibody-drug conjugatesB lymphoid malignancyB-Cell Acute Lymphoblastic LeukemiaB-Cell Antigen ReceptorB-Cell LeukemiaB-Cell LymphomasB-Cell NeoplasmB-Cell NonHodgkins LymphomaB-LymphocytesBRAF geneCRISPR/Cas technologyCell Cycle ArrestCell DeathCell membraneCell surfaceCellsClinicalClone CellsComplementComplexCytoplasmCytoplasmic TailDiseaseDrug TargetingDrug resistanceEquilibriumFOXM1 geneFeedbackGenesGeneticGenetic TranscriptionHairy Cell LeukemiaHeterogeneityHodgkin DiseaseHumanHuman Herpesvirus 4Human Herpesvirus 8IL2RA geneImmune systemImmunotherapyIndividualInterleukin 2 ReceptorLate EffectsLesionLymphomaLymphoma cellMalignant - descriptorMalignant Childhood NeoplasmMalignant NeoplasmsMeasuresMediastinalMediatingMembraneModelingMusNewly DiagnosedOncogenesOncogenicOncoproteinsOutcomeOutputPathway interactionsPatientsPersonsPh+ ALLPharmaceutical PreparationsPharmacologyPharmacotherapyPhosphoric Monoester HydrolasesPhosphorylationPreclinical TestingProtocols documentationReceptor SignalingRegulationRelapseReporterRoleSafetySamplingSignal PathwaySignal TransductionSurfaceSurvival RateSystemT-LymphocyteTP53 geneTestingTherapeuticTherapeutic InterventionToxic effectTransplant RecipientsTumor SubtypeUltraviolet RaysUmbilical Cord BloodValidationViralVirusWaldenstrom MacroglobulinemiaXenograft procedureacute toxicitybasechemotherapychimeric antigen receptorcohortdesignengineered T cellsexperimental studyimproved outcomein vivo evaluationinhibitorlarge cell Diffuse non-Hodgkin&aposs lymphomaleukemia/lymphomamimicrymouse modelmultidrug resistance inhibition therapynew therapeutic targetoptogeneticspharmacokinetics and pharmacodynamicsrecruitresponseselective expressionside effectsingle cell analysissurvivorshiptumor
项目摘要
PROJECT SUMMARY
B cells critically depend on continuous survival and proliferation signals from a functional B cell receptor (BCR).
Likewise, in ~50% of B cell malignancies, the tumor clone is driven by an oncogenic BCR-mimic. Oncogenic
mimics of BCR-dependent proliferation and survival signals include BCR-ABL1 (Ph+ ALL), viral oncoproteins (e.g.
EBV), RAS- and NF-κB-pathway activating lesions (Hodgkin's lymphoma, PMBL, ABC-DLBCL, hairy cell
leukemia, Waldenström's macroglobulinemia). In preliminary studies, we found that CD25 is selectively expressed
on malignant B cell clones driven by oncogenic BCR-mimics. While CD25 functions as IL2 receptor α-chain on T
cells, we recently discovered that CD25 is a critical feedback regulator of BCR signaling and oncogenic BCR-
mimics in human B cell tumors. Genetic experiments demonstrated that CD25 is critical for the initiation of B cell
leukemia and lymphoma in transplant recipients. Surface expression is rapidly induced by activity of BTK and
PKCδ downstream of the BCR and induced by FOXM1 and NF-κB at the transcriptional level. CD25 then recruits
an inhibitory complex to the cell membrane to reduce and recalibrate BCR signaling or oncogenic mimicry of
BCR-signaling. Analysis of three clinical cohorts revealed that high expression levels of CD25 are associated with
poor clinical outcome in various B cell malignancies. While CD25 expression is associated with drug-resistance,
inhibition of CD25 or disabling of CD25-dependent feedback control sensitizes multiple B cell malignancies to
conventional drug-treatment.
Based on these and other findings, we propose three Aims to (1) elucidate mechanisms of CD25 regulation, (2)
explore usefulness of pharmacological subversion of CD25-mediated feedback control and (3) targeted
eradication of CD25+ cells by CART25 cells and antibody-drug conjugates (ADC) as therapeutic adjuvant.
项目总结
B细胞在很大程度上依赖于功能正常的B细胞受体(BCR)的持续存活和增殖信号。
同样,在大约50%的B细胞恶性肿瘤中,肿瘤克隆是由致癌的BCR模拟物驱动的。致癌作用
BCR依赖的增殖和生存信号的模拟物包括BCR-ABL1(Ph+ALL)、病毒癌蛋白(例如:BCR-ABL1)、BCR-ABL1(Ph+ALL)和BCR-ABL1。
EB病毒)、RAS和NF-κB途径激活性病变(霍奇金淋巴瘤、粒细胞淋巴瘤、ABC-DLBCL、毛细胞
白血病、Waldenström巨球蛋白血症)。在初步研究中,我们发现CD25被选择性地表达
致癌BCR-模拟物驱动的恶性B细胞克隆的研究而CD25在T细胞上作为IL_2受体α链发挥作用
细胞,我们最近发现CD25是bcr信号和致癌bcr的关键反馈调节因子。
在人类B细胞肿瘤中模拟。遗传学实验证明CD25在B细胞的启动中起关键作用
移植受者的白血病和淋巴瘤。BTK和BTK的活性可快速诱导细胞表面表达
PKCδ位于bcr下游,在转录水平上受FOXM1和NF-κB诱导。CD25然后招募
一种对细胞膜的抑制复合体,以减少和重新校准bcr信号或致癌模拟
BCR-信令。对三个临床队列的分析表明,CD25的高表达水平与
各种B细胞恶性肿瘤的临床转归较差。虽然CD25的表达与耐药性有关,
抑制CD25或禁用CD25依赖的反馈控制使多种B细胞恶性肿瘤对
常规药物治疗。
基于这些和其他发现,我们提出了三个目标:(1)阐明CD25的调控机制;(2)
探索药物颠覆CD25介导的反馈控制的有用性和(3)有针对性
CART25细胞和抗体-药物结合物(ADC)作为治疗佐剂清除CD25+细胞。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Origins of the human B-cell lineage.
人类 B 细胞谱系的起源。
- DOI:10.1182/blood.2019002573
- 发表时间:2019
- 期刊:
- 影响因子:20.3
- 作者:Müschen,Markus
- 通讯作者:Müschen,Markus
Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia.
在急性淋巴细胞白血病中,含瓣膜蛋白/p97作为新型治疗靶标。
- DOI:10.1016/j.neo.2017.08.001
- 发表时间:2017-10
- 期刊:
- 影响因子:0
- 作者:Gugliotta G;Sudo M;Cao Q;Lin DC;Sun H;Takao S;Le Moigne R;Rolfe M;Gery S;Müschen M;Cavo M;Koeffler HP
- 通讯作者:Koeffler HP
Metabolic determinants of B-cell selection.
- DOI:10.1042/bst20201316
- 发表时间:2021-07
- 期刊:
- 影响因子:3.9
- 作者:L. Chan;Eamon Aghania;Etienne Leveille;M. Müschen
- 通讯作者:L. Chan;Eamon Aghania;Etienne Leveille;M. Müschen
Metabolic Gatekeepers of Pathological B Cell Activation.
- DOI:10.1146/annurev-pathol-061020-050135
- 发表时间:2020-12
- 期刊:
- 影响因子:0
- 作者:Teresa Sadras;L. Chan;G. Xiao;M. Müschen
- 通讯作者:Teresa Sadras;L. Chan;G. Xiao;M. Müschen
Lineage-Specific Genes Are Prominent DNA Damage Hotspots during Leukemic Transformation of B Cell Precursors.
- DOI:10.1016/j.celrep.2017.01.057
- 发表时间:2017-02-14
- 期刊:
- 影响因子:8.8
- 作者:Boulianne B;Robinson ME;May PC;Castellano L;Blighe K;Thomas J;Reid A;Müschen M;Apperley JF;Stebbing J;Feldhahn N
- 通讯作者:Feldhahn N
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Markus Müschen其他文献
Markus Müschen的其他文献
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{{ truncateString('Markus Müschen', 18)}}的其他基金
Targeting GSK3B in refractory B-cell malignancies
靶向 GSK3B 治疗难治性 B 细胞恶性肿瘤
- 批准号:
10720232 - 财政年份:2023
- 资助金额:
$ 16.67万 - 项目类别:
Targeted activation of autoimmune checkpoints in B cell malignancies
B 细胞恶性肿瘤中自身免疫检查点的靶向激活
- 批准号:
10339747 - 财政年份:2021
- 资助金额:
$ 16.67万 - 项目类别:
Metabolic basis of B cell lineage leukemia relapse
B细胞系白血病复发的代谢基础
- 批准号:
10339722 - 财政年份:2021
- 资助金额:
$ 16.67万 - 项目类别:
CD25-mediated feedback control of BCR-signaling and its oncogenic mimics
CD25 介导的 BCR 信号反馈控制及其致癌模拟物
- 批准号:
10339650 - 财政年份:2021
- 资助金额:
$ 16.67万 - 项目类别:
CD25-mediated feedback control of BCR-signaling and its oncogenic mimics
CD25 介导的 BCR 信号反馈控制及其致癌模拟物
- 批准号:
10199948 - 财政年份:2021
- 资助金额:
$ 16.67万 - 项目类别:
Targeting oncogenic TCR signaling in PTCL
靶向 PTCL 中的致癌 TCR 信号传导
- 批准号:
10005239 - 财政年份:2019
- 资助金额:
$ 16.67万 - 项目类别:
Targeting oncogenic TCR signaling in PTCL
靶向 PTCL 中的致癌 TCR 信号传导
- 批准号:
10249203 - 财政年份:2019
- 资助金额:
$ 16.67万 - 项目类别:
Targeting oncogenic TCR signaling in PTCL
靶向 PTCL 中的致癌 TCR 信号传导
- 批准号:
10477022 - 财政年份:2019
- 资助金额:
$ 16.67万 - 项目类别:
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