# CD25-mediated feedback control of BCR-signaling and its oncogenic mimics

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $169,192

## Abstract

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.

## Key facts

- **NIH application ID:** 9928015
- **Project number:** 5R01CA213138-04
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Markus Muschen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,192
- **Award type:** 5
- **Project period:** 2017-06-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928015

## Citation

> US National Institutes of Health, RePORTER application 9928015, CD25-mediated feedback control of BCR-signaling and its oncogenic mimics (5R01CA213138-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928015. Licensed CC0.

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