Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia

  • Mol Cancer. 2023 Dec 4;22(1):196. doi: 10.1186/s12943-023-01907-7.
Nuria Tubío-Santamaría  1  2 ,  Ashok Kumar Jayavelu  3  4 ,  Tina M Schnoeder  1  2 ,  Theresa Eifert  1  2 ,  Chen-Jen Hsu  1  2 ,  Florian Perner  1 ,  Qirui Zhang  1 ,  Daniela V Wenge  5 ,  Fynn M Hansen  3 ,  Joanna M Kirkpatrick  6 ,  Nidhi Jyotsana  7 ,  Steven W Lane  8 ,  Björn von Eyss  2 ,  Aniruddha J Deshpande  9 ,  Michael W M Kühn  10 ,  Juerg Schwaller  11 ,  Clemens Cammann  12 ,  Ulrike Seifert  12 ,  Frédéric Ebstein  13 ,  Elke Krüger  13 ,  Andreas Hochhaus  14 ,  Michael Heuser  15 ,  Alessandro Ori  2 ,  Matthias Mann  3 ,  Scott A Armstrong  5 ,  Florian H Heidel  16  17  18
Affiliations
  • 1. Innere Medizin C, Universitätsmedizin Greifswald, 17475, Greifswald, Germany.
  • 2. Leibniz Institute On Aging, Fritz-Lipmann Institute, 07745, Jena, Germany.
  • 3. Max-Planck-Institute of Biochemistry, Munich, Germany.
  • 4. Proteomics and Cancer Cell Signaling Group, DKFZ, Heidelberg, Germany.
  • 5. Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard University, Boston, MA, 02215, USA.
  • 6. Independent consultant, London, UK.
  • 7. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • 8. Queensland Institute for Medical Research (QIMR), Brisbane, Australia.
  • 9. Sanford Burnham Research Institute, San Diego, USA.
  • 10. Medizinische Klinik 3, Hämatologie, Onkologie und Pneumologie, Universitätsmedizin Mainz, Mainz, Germany.
  • 11. Department of Biomedicine, University Children's Hospital of Basel, Basel, Switzerland.
  • 12. Friedrich Loeffler-Institut für Medizinische Mikrobiologie - Virologie, Universitätsmedizin Greifswald, 17475, Greifswald, Germany.
  • 13. Department of Biochemistry, Universitätsmedizin Greifswald, 17475, Greifswald, Germany.
  • 14. Innere Medizin 2, Universitätsklinikum Jena, Jena, Germany.
  • 15. Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany.
  • 16. Innere Medizin C, Universitätsmedizin Greifswald, 17475, Greifswald, Germany. [email protected].
  • 17. Leibniz Institute On Aging, Fritz-Lipmann Institute, 07745, Jena, Germany. [email protected].
  • 18. Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany. [email protected].
PMID: 38049829 DOI: 10.1186/s12943-023-01907-7
Abstract

Pharmacologic targeting of chromatin-associated protein complexes has shown significant responses in KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) but resistance frequently develops to single agents. This points to a need for therapeutic combinations that target multiple mechanisms. To enhance our understanding of functional dependencies in KMT2A-r AML, we have used a proteomic approach to identify the catalytic immunoproteasome subunit PSMB8 as a specific vulnerability. Genetic and pharmacologic inactivation of PSMB8 results in impaired proliferation of murine and human leukemic cells while normal hematopoietic cells remain unaffected. Disruption of immunoproteasome function drives an increase in transcription factor BASP1 which in turn represses KMT2A-fusion protein target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, synergistically reduces leukemia in human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selective disruption of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. These data demonstrate that the immunoproteasome is a relevant therapeutic target in AML and that targeting the immunoproteasome in combination with Menin-inhibition could be a novel approach for treatment of KMT2A-r AML.

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