2. Academic Validation
  3. Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia

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

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. heidel.florian@mh-hannover.de.
  • 17 Leibniz Institute On Aging, Fritz-Lipmann Institute, 07745, Jena, Germany. heidel.florian@mh-hannover.de.
  • 18 Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany. heidel.florian@mh-hannover.de.
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z