mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia
10 affiliations
- 1Department of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
- 2Doctoral School of Translational Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland
- 3Department of Genetic Predisposition to Cancer, Medical University of Lodz, Lodz, Poland
- 4Department of Pathology, Medical University of Warsaw, Warsaw, Poland
- 5Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
- 6Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
- 7Red Española de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain
- 8Hugh and Josseline Langmuir Centre for Myeloma Research, Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK
- 9Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
- 10Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
Abstract
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT–FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.
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BibTeX
@article{dabkowska2026mtorc1,
title = {{mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia}},
author = {Agnieszka Dąbkowska and Martyna Janowska and Agata Pastorczak and Krzysztof Domka and Zuzanna Nowicka and Zuzanna Urbanska and Weronika Zając and Mikołaj Bugajewski and Julia Grzybowska and Pola Pruchniak and Klaudyna Fidyt and Wojciech Fendler and Jason Taslim and Nicholas T. Crump and Alexey Ushmorov and Elzbieta Patkowska and Malgorzata Firczuk},
journal = {Leukemia},
year = {2026},
month = aug,
doi = {10.1038/s41375-026-03093-z},
url = {https://doi.org/10.1038/s41375-026-03093-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia
AU - Agnieszka Dąbkowska
AU - Martyna Janowska
AU - Agata Pastorczak
AU - Krzysztof Domka
AU - Zuzanna Nowicka
AU - Zuzanna Urbanska
AU - Weronika Zając
AU - Mikołaj Bugajewski
AU - Julia Grzybowska
AU - Pola Pruchniak
AU - Klaudyna Fidyt
AU - Wojciech Fendler
AU - Jason Taslim
AU - Nicholas T. Crump
AU - Alexey Ushmorov
AU - Elzbieta Patkowska
AU - Malgorzata Firczuk
PY - 2026
DA - 2026/08/19
JO - Leukemia
DO - 10.1038/s41375-026-03093-z
UR - https://doi.org/10.1038/s41375-026-03093-z
AB - B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT–FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.
SN - 0887-6924
SN - 1476-5551
ER -