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 #
5R01CA213138-02
Application #
9493452
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Venkatachalam, Sundaresan
Project Start
2017-06-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Xiao, Gang; Chan, Lai N; Klemm, Lars et al. (2018) B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 173:470-484.e18
Martín-Lorenzo, Alberto; Auer, Franziska; Chan, Lai N et al. (2018) Loss of Pax5 Exploits Sca1-BCR-ABLp190 Susceptibility to Confer the Metabolic Shift Essential for pB-ALL. Cancer Res 78:2669-2679
Wang, Lili; Müschen, Markus (2018) Portending death in germinal centers - when B cells know their time is up. Cell Res 28:5-6
Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara et al. (2017) Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. J Clin Invest 127:2392-2406
Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914
Gugliotta, Gabriele; Sudo, Makoto; Cao, Qi et al. (2017) Valosin-Containing Protein/p97 as a Novel Therapeutic Target in Acute Lymphoblastic Leukemia. Neoplasia 19:750-761
Cao, Qi; Zhao, Xuan; Bai, Jingwen et al. (2017) Circadian clock cryptochrome proteins regulate autoimmunity. Proc Natl Acad Sci U S A 114:12548-12553
Chan, Lai N; Chen, Zhengshan; Braas, Daniel et al. (2017) Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542:479-483
Xu, Liang; Chen, Ye; Dutra-Clarke, Marina et al. (2017) BCL6 promotes glioma and serves as a therapeutic target. Proc Natl Acad Sci U S A 114:3981-3986
Katerndahl, Casey D S; Heltemes-Harris, Lynn M; Willette, Mark J L et al. (2017) Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nat Immunol 18:694-704

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