ArticleMolecular cancer2023
Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia.
Article in Molecular cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 13 citations in OpenAlex.
- Effect of the Proteasome Inhibitor, Bortezomib, on Histone Modifications in Human Leukemic Cell Lines.International journal of molecular sciences · 2026Article
- Intracellular Activation of Dual-Pharmacophore Artezomib Enhances Selective Cytotoxicity in Hematologic Malignancies.Journal of medicinal chemistry · 2026Article
- Reactivation of the silencedProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Targeting the roots of myeloid malignancies with T cell receptors.Nature reviews. Cancer · 2025Review
- Current landscape of the immunoproteasome: implications for disease and therapy.Cell death discovery · 2025Review
- PSMB10 maintains the stemness of chemotherapeutic drug-resistant leukemia cells by inhibiting senescence and cytotoxic T lymphocyte-mediated killing in a ubiquitinated degradation manner.Journal of experimental & clinical cancer research : CR · 2025Article
- Ubiquitin-conjugating enzyme UBE2N modulates proteostasis in immunoproteasome-positive acute myeloid leukemia.The Journal of clinical investigation · 2025Article
- From oncogenesis to prognosis: the roles of the immunoproteasome in cancer.Frontiers in immunology · 2025Review
- The Proteasome-Family-Members-Based Prognostic Model Improves the Risk Classification for Adult Acute Myeloid Leukemia.Biomedicines · 2024Article
- Menin in Cancer.Genes · 2024Review
- Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition inInternational journal of molecular sciences · 2024Article
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Authors and funding
26 authors at 12 institutions in 4 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.