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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：
10199948
负责人：
Markus Müschen
金额：
$ 38.32万
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/10199948
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 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/antagonist 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.

项目总结