Similar Datasets
Project description: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.
| S-EPMC10694946 | biostudies-literature
Project description:Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in AML. Early clinical trials in MLL-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of MLL-fusions in acute myeloid leukemia, we identify the catalytic immunoproteasome subunit PSMB8 as an oncogene-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 results in cellular enrichment of transcription factor BASP1, and consecutive repression of MLL-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selectivity of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate AML harboring MLL-rearrangements.
2023-12-13 | GSE225374 | GEO
Project description:Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in AML. Early clinical trials in MLL-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of MLL-fusions in acute myeloid leukemia, we identify the catalytic immunoproteasome subunit PSMB8 as an oncogene-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 results in cellular enrichment of transcription factor BASP1, and consecutive repression of MLL-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selectivity of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate AML harboring MLL-rearrangements.
2023-12-13 | GSE227474 | GEO
Project description:Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in AML. Early clinical trials in MLL-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of MLL-fusions in acute myeloid leukemia, we identify the catalytic immunoproteasome subunit PSMB8 as an oncogene-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 results in cellular enrichment of transcription factor BASP1, and consecutive repression of MLL-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selectivity of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate AML harboring MLL-rearrangements.
2023-12-13 | GSE225356 | GEO
Project description:Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in AML. Early clinical trials in MLL-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of MLL-fusions in acute myeloid leukemia, we identify the catalytic immunoproteasome subunit PSMB8 as an oncogene-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 results in cellular enrichment of transcription factor BASP1, and consecutive repression of MLL-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selectivity of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate AML harboring MLL-rearrangements.
2023-12-13 | GSE225315 | GEO
Project description:Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia
| PRJNA935383 | ENA
Project description:Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in acute myeloid leukemia (AML). Early clinical trials in KMT2A-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of KMT2A-fusions in AML, we identify the catalytic immunoproteasome subunit PSMB8 as a KMT2A-complex-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 results in cellular enrichment of transcription factor BASP1, and consecutive repression of KMT2A-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary 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. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate KMT2A-complex driven AML.
2024-01-26 | PXD041245 | Pride
Project description:Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [Cut & Tag]
| PRJNA945335 | ENA
Project description:Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [ATAC-seq]
| PRJNA935362 | ENA
Project description:Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [RNA-seq II]
| PRJNA935341 | ENA