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-?B-pathway activating lesions (Hodgkin's lymphoma, PMBL, ABC-DLBCL, hairy cell leukemia, Waldenstrm'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 ?-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 PKC? downstream of the BCR and induced by FOXM1 and NF-?B 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.

Public Health Relevance

We recently revealed that CD25 functions as a critical feedback regulator of B cell receptor (BCR) and oncogenic mimics of BCR signaling in aggressive B cell malignancies. CD25-dependent feedback regulation is induced by oncogenic mimics of BCR signaling (e.g. BCR-ABL1, EBV-oncoproteins, BRAF, activating NF-?B pathway lesions), enables robustness of oncogenic signaling and is critical for the initiation of disease in transplant recipients. We hypothesize that CD25-dependent feedback control of oncogenic signaling represents a novel drug-target in aggressive B cell malignancies. We propose three Aims to (1) elucidate mechanisms of CD25 regulation, (2) explore usefulness of pharmacological subversion of CD25-mediated feedback control and (3) CD25 as target for immunotherapy (CART25) and antibody-drug conjugates (ADC).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA213138-01
Application #
9220612
Study Section
Special Emphasis Panel (ZRG1-BMCT-C (01)S)
Program Officer
Forry, Suzanne L
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
1
Fiscal Year
2017
Total Cost
$395,738
Indirect Cost
$166,988
Name
Beckman Research Institute/City of Hope
Department
Type
Research Institutes
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
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