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

Nuria Tubío-Santamaría1,2, Ashok Kumar Jayavelu3,4, Tina M Schnoeder1,2

  • 1Innere Medizin C, Universitätsmedizin Greifswald, 17475, Greifswald, Germany.

Molecular Cancer
|December 4, 2023
PubMed

Insights

Targeting the immunoproteasome, specifically PSMB8, shows promise for KMT2A-rearranged acute myeloid leukemia (AML). Combining immunoproteasome inhibitors with Menin-inhibitors offers a novel therapeutic strategy for AML treatment.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) shows responses to chromatin-targeting drugs, but resistance is common.
  • Combination therapies are needed to overcome resistance and improve treatment efficacy in KMT2A-r AML.
  • Understanding functional dependencies is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To identify specific vulnerabilities in KMT2A-r AML using a proteomic approach.
  • To investigate the role of the immunoproteasome, particularly PSMB8, in KMT2A-r AML.
  • To evaluate the therapeutic potential of targeting PSMB8, alone and in combination with Menin-inhibitors.

Main Methods:

  • Proteomic analysis to identify drug targets.
  • Genetic and pharmacologic inactivation of PSMB8 in murine and human cell models.
  • Assessment of leukemic cell proliferation and normal hematopoietic cell function.
  • Evaluation of BASP1 transcription factor levels and its effect on KMT2A-fusion target genes.
  • Combination studies with Menin-inhibitors in xenograft models.

Main Results:

  • PSMB8 was identified as a specific vulnerability in KMT2A-r AML.
  • PSMB8 inactivation impaired leukemic cell proliferation without affecting normal hematopoietic cells.
  • Disruption of immunoproteasome function increased BASP1, repressing KMT2A-fusion target genes.
  • Pharmacologic PSMB8 targeting enhanced Menin-inhibitor efficacy and reduced leukemia burden.
  • Combination therapy showed preserved activity against Menin-inhibitor resistance mutations.

Conclusions:

  • The immunoproteasome is a relevant therapeutic target in KMT2A-r AML.
  • Selective disruption of proteostasis alters transcription factor abundance and oncogenic networks.
  • Combining immunoproteasome inhibition with Menin-inhibition presents a novel therapeutic approach for KMT2A-r AML.
  • This strategy offers potential for overcoming Menin-inhibitor resistance.

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