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.

项目概要 B 细胞严重依赖于功能性 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 BCR 模拟物驱动的。 BCR 依赖性增殖和生存信号的模拟物包括 BCR-ABL1 (Ph+ ALL)、病毒癌蛋白（例如 EBV)、RAS 和 NF-κB 通路激活病变（霍奇金淋巴瘤、PMBL、ABC-DLBCL、毛细胞在初步研究中，我们发现 CD25 是选择性表达的。 CD25 作用于 T 上的 IL2 受体 α 链。细胞，我们最近发现 CD25 是 BCR 信号传导和致癌 BCR-的关键反馈调节因子基因实验表明，CD25 对于 B 细胞的启动至关重要。 BTK 和 BTK 的活性可快速诱导移植受者的白血病和淋巴瘤。 BCR 下游的 PKCδ 在转录水平上由 FOXM1 和 NF-κB 诱导，然后招募 CD25。细胞膜的抑制复合物，可减少和重新校准 BCR 信号传导或致癌模拟对三个临床队列的 BCR 信号分析表明，CD25 的高表达水平与相关。各种 B 细胞恶性肿瘤的临床结果不佳，而 CD25 表达与耐药性相关。抑制 CD25 或禁用 CD25 依赖性反馈控制可使多种 B 细胞恶性肿瘤敏感常规药物治疗。基于这些和其他发现，我们提出了三个目标：(1) 阐明 CD25 调节机制，(2) 探索药理学颠覆 CD25 介导的反馈控制的有用性和 (3) 有针对性的 CART25细胞和抗体药物偶联物（ADC）作为治疗佐剂根除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：
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