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：
Markus Müschen
金额：
$ 16.67万
依托单位：
YALE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10455511
关键词：
ABL1 gene Ablation Acute Lymphocytic Leukemia Adjuvant Adjuvant Chemotherapy Antibody-drug conjugates B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Antigen Receptor B-Cell Leukemia B-Cell Lymphomas B-Cell Neoplasm B-Cell NonHodgkins Lymphoma B-Lymphocytes BRAF gene CRISPR/Cas technology Cell Cycle Arrest Cell Death Cell membrane Cell surface Cells Clinical Clone Cells Complement Complex Cytoplasm Cytoplasmic Tail Disease Drug Targeting Drug resistance Equilibrium FOXM1 gene Feedback Genes Genetic Genetic Transcription Hairy Cell Leukemia Heterogeneity Hodgkin Disease Human Human Herpesvirus 4 Human Herpesvirus 8 IL2RA gene Immune system Immunotherapy Individual Interleukin 2 Receptor Late Effects Lesion Lymphoma Lymphoma cell Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Measures Mediastinal Mediating Membrane Modeling Mus Newly Diagnosed Oncogenes Oncogenic Oncoproteins Outcome Output Pathway interactions Patients Persons Ph+ ALL Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphoric Monoester Hydrolases Phosphorylation Preclinical Testing Protocols documentation Receptor Signaling Regulation Relapse Reporter Role Safety Sampling Signal Pathway Signal Transduction Surface Survival Rate System T-Lymphocyte TP53 gene Testing Therapeutic Therapeutic Intervention Toxic effect Transplant Recipients Tumor Subtype Ultraviolet Rays Umbilical Cord Blood Validation Viral Virus Waldenstrom Macroglobulinemia Xenograft procedure acute toxicity base chemotherapy chimeric antigen receptor cohort design engineered T cells experimental study improved outcome in vivo evaluation inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma leukemia/lymphoma mimicry mouse model multidrug resistance inhibition therapy new therapeutic target optogenetics pharmacokinetics and pharmacodynamics recruit response selective expression side effect single cell analysis survivorship tumor

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.

项目摘要 B细胞严格依赖于功能性B细胞受体（BCR）的连续存活和增殖信号。同样，在约50％的B细胞恶性肿瘤中，肿瘤克隆由致癌BCR模拟驱动。致癌 BCR依赖性增殖和存活信号的模仿包括BCR-ABL1（pH+ ALL），病毒癌蛋白（例如， EBV），RAS和NF-κB-Pathway激活病变（Hodgkin的淋巴瘤，PMBL，ABC-DLBCL，毛茸茸的细胞白血病，华尔登斯特氏菌的大球蛋白血症）。在初步研究中，我们发现CD25选择性表达在由致癌BCR模拟驱动的恶性B细胞克隆上。而CD25在T上充当IL2受体α链细胞，我们最近发现CD25是BCR信号传导和致癌BCR-的关键反馈调节剂模仿人B细胞肿瘤。遗传实验表明，CD25对于B细胞的主动性至关重要移植受者的白血病和淋巴瘤。 BTK的活性迅速诱导了表面表达 BCR下游的PKCδ，并由FOXM1和NF-κB在转录水平诱导。 CD25然后招募细胞膜的抑制复合物，以减少和重新校准BCR信号传导或致癌模仿 BCR信号。对三个临床队列的分析表明，CD25的高表达水平与各种B细胞恶性肿瘤中的临床结果差。虽然CD25表达与药物抗性有关抑制CD25或禁用CD25依赖性反馈控制灵敏度多重B细胞恶性肿瘤常规药物治疗。基于这些发现和其他发现，我们提出了三个目标，以（1）阐明CD25调节的机制，（2）探索CD25介导的反馈控制的药物颠覆和（3）的有用性 CART25细胞和抗体 - 药物结合物（ADC）消除CD25+细胞，以调节。

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：
Blood
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.

DOI：
10.1016/j.neo.2017.08.001
发表时间：
2017-10
期刊：
Neoplasia (New York, N.Y.)
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：
Biochemical Society transactions
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：
Annual review of pathology
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：
Cell reports
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