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

Author:

Tubío-Santamaría Nuria,Jayavelu Ashok Kumar,Schnoeder Tina M.,Eifert Theresa,Hsu Chen-Jen,Perner Florian,Zhang Qirui,Wenge Daniela V.,Hansen Fynn M.,Kirkpatrick Joanna M.,Jyotsana Nidhi,Lane Steven W.,von Eyss Björn,Deshpande Aniruddha J.,Kühn Michael W. M.,Schwaller Juerg,Cammann Clemens,Seifert Ulrike,Ebstein Frédéric,Krüger Elke,Hochhaus Andreas,Heuser Michael,Ori Alessandro,Mann Matthias,Armstrong Scott A.,Heidel Florian H.

Abstract

AbstractPharmacologic 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.

Funder

Deutsche Forschungsgemeinschaft

Wilhelm Sander-Stiftung

Universität Greifswald

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology,Molecular Medicine

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