Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy
Uta M. Demel,
Matthias Wirth,
Schayan Yousefian,
Le Zhang,
Konstandina Isaakidis,
Judith Dönig,
Marlitt Böger,
Nikita Singh,
Hazal Köse,
Simon Haas,
Stefan Müller,
Markus Schick,
Ulrich Keller
Affiliations
Uta M. Demel
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin
Matthias Wirth
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Schayan Yousefian
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin
Le Zhang
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Konstandina Isaakidis
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Judith Dönig
Institute of Biochemistry II, Goethe University Frankfurt, Medical School, 60590 Frankfurt
Marlitt Böger
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Nikita Singh
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Hazal Köse
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Simon Haas
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, 10117 Berlin, Germany; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ) and DKFZZMBH Alliance, 69120 Heidelberg
Stefan Müller
Institute of Biochemistry II, Goethe University Frankfurt, Medical School, 60590 Frankfurt
Markus Schick
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin
Ulrich Keller
Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg
Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small-molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a preclinical murine in vivo model of MYC-driven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B cells as well as cytotoxic and memory T cells, subsets that are attributed a key role within a coordinated anti-tumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of BCL causing massive remodeling of the normal B-cell and T-cell compartment.
