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Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [Cut & Tag]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227474 | GEO | 2023/12/13

REPOSITORIES: GEO

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Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [ATAC-seq]

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

Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [RNA-seq II]

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Immunoproteasome function maintains oncogenic gene expression in KMT2a-rearranged leukemia [RNA-seq I]

2023-12-13 | GSE225315 | GEO

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

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

Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo

Project description:Chromosomal translocations affecting Mixed Lineage Leukemia (MLL) gene result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report development of novel, highly potent and orally bioavailable small molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, show their profound effects in MLL leukemia cells and substantial survival benefit in mice models of MLL leukemia. Finally, we demonstrate efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate for the first time that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

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Targeting the MLL complex in castration-resistant prostate cancer [expression]

Project description:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer. ASH2L / Menin / MLL1 were knocked down using shRNA /siRNA in two prostate cancer cell lines, VCaP and LNCaP.

2015-03-02 | E-GEOD-60836 | biostudies-arrayexpress

Expression data from human AML cell lines

Project description:Pediatric Acute Myeloid Leukemia (AML) is an aggressive and poor prognosis malignancy for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been reported. Recent studies reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulated expression of genes with relevant roles in cancer development. Such modifications in transcriptional program impact on further treatments, inducing a strong sensitization to Sorafenib, with increased apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. We used microarrays to define differential regulation of gene expression in AML cell lines with or without MLL gene rearrangements following pharmacologic inhibition of DOT1L.

2020-07-24 | GSE144638 | GEO

Synergistic Targeting of FLT3 Mutations in AML via Combined Menin-MLL and FLT3 Inhibition

Project description:The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1 mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL inhibition with specific small molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mut FLT3mut AML showed significantly better responses to combined Menin and FLT3 inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

2020-07-01 | GSE144759 | GEO

Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia

Project description:Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known how mutant NPM1 (NPM1mut) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1mut AML. Using a CRISPR-Cas9 genome editing domain screen, we show NPM1mut AML to be exceptionally dependent on the menin binding site in MLL1. Pharmacological small-molecule inhibition of the menin-MLL protein interaction had profound anti-leukemic activity in human and murine models of NPM1mut AML in vitro and in vivo. Combined pharmacological inhibition of menin-MLL and DOT1L resulted in dramatic suppression of HOX and FLT3 expression, induction of differentiation, and superior activity against NPM1mut leukemia. Together, MLL1 and DOT1L are chromatin regulators that control HOX, MEIS1 and FLT3 expression and are therapeutic targets in NPM1mut AML. Combinatorial small-molecule inhibition has synergistic on target activity and constitutes a novel therapeutic concept for this common AML subtype. RNA sequencing data of the human AML cell lines OCI-AML2 and OCI-AML3 comparing EPZ004777 [10ÂµM] drug treatment versus DMSO vehicle control; experiments performed in biological triplicates.

2016-08-22 | E-GEOD-85107 | biostudies-arrayexpress

A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia

Project description:Inhibition of the Menin (encoded by MEN1) and MLL1 (KMT2A) protein-protein interaction has been proposed as a potential targeted therapeutic strategy for MLL-rearranged (MLL-r) leukemia. We sought to develop more potent and selective Menin-MLL1 interaction inhibitors that are effective in vitro and in vivo to directly assess potential therapeutic opportunities. Structure-based design yielded the potent, highly selective and orally-bioavailable small molecule inhibitor VTP-50469. Human cell lines carrying MLL-rearrangements were highly sensitive and selectively responsive to treatment with VTP-50469. VTP-50469 displaced Menin from high molecular weight protein complexes and inhibited chromatin occupancy of MLL1 at select target genes. Loss of MLL1 binding led to specific changes in gene expression, cellular differentiation, and apoptosis. Mice engrafted with leukemia cells isolated from patients with either MLL-r AML or MLL-r ALL showed dramatic reductions of leukemia burden and prolonged survival when treated with VTP-50469. Remarkably, multiple mice engrafted with MLL-r ALL remained disease free greater than 1 year following cessation of treatment. Therefore, inhibition of the Menin-MLL1 interaction with VTP-50469 is highly effective in patient-derived xenograft (PDX) models of human MLL-r AML and MLL-r ALL which supports rapid translation of this approach to clinical trials. This submission represents the scRNAseq component of the study.

2019-02-28 | GSE127298 | GEO

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