The menin inhibitor SNDX-5613 for KMT2A rearranged or NPM1 mutant leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA895062 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22069900_1.fastq.gz | Fastqsanger.gz | |||
| SRR22069900_2.fastq.gz | Fastqsanger.gz | |||
| SRR22069901_1.fastq.gz | Fastqsanger.gz | |||
| SRR22069901_2.fastq.gz | Fastqsanger.gz | |||
| SRR22069890_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependency in acute leukaemia caused by either rearrangement of KMT2A or mutation in Nucleophosmin 1(NPM1). KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin–KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
2023-03-01 | GSE216730 | GEO
Project description:The chromatin adaptor protein Menin (MEN1) is required by acute leukemias driven by mixed lineage leukemia 1 gene rearrangements (KMT2A-r) for sustained leukemogenesis. Menin inhibitors (MIs), which disrupt the Menin-KMT2A interface leading to downregulation of Menin-KMT2A oncogenic transcriptional programs, have shown promising results in recent clinical trials treating acute myeloid leukemia (AML). Decreased Menin protein stability has been observed following treatment with several MIs though proteasomal degradation, though the biological mechanisms that control Menin stability are not well understood. Here we interrogate and compare five clinical MIs and two pre-clinical compounds to characterize the mechanism by which MIs induce Menin degradation and demonstrate that the loss of the Menin-KMT2A interaction results in decreased protein stability of Menin and KMT2A. We have identified the HECT E3 ubiquitin ligase UBR5 as a regulator of Menin protein stability and demonstrate that UBR5 binds to similar sites as the Menin/KMT2A complex on chromatin. Loss of UBR5 leads to transcriptional rescue of Menin-KMT2A target genes leading to decreased sensitivity to all MIs. Thus, we present UBR5 as an important regulator of Menin/KMT2A complex stability and Menin destabilization/subcellular localization as a designable feature of Menin inhibition targeting KMT2A-r leukemias.
2025-08-01 | GSE299103 | GEO
Project description:The chromatin adaptor protein Menin (MEN1) is required by acute leukemias driven by mixed lineage leukemia 1 gene rearrangements (KMT2A-r) for sustained leukemogenesis. Menin inhibitors (MIs), which disrupt the Menin-KMT2A interface leading to downregulation of Menin-KMT2A oncogenic transcriptional programs, have shown promising results in recent clinical trials treating acute myeloid leukemia (AML). Decreased Menin protein stability has been observed following treatment with several MIs though proteasomal degradation, though the biological mechanisms that control Menin stability are not well understood. Here we interrogate and compare five clinical MIs and two pre-clinical compounds to characterize the mechanism by which MIs induce Menin degradation and demonstrate that the loss of the Menin-KMT2A interaction results in decreased protein stability of Menin and KMT2A. We have identified the HECT E3 ubiquitin ligase UBR5 as a regulator of Menin protein stability and demonstrate that UBR5 binds to similar sites as the Menin/KMT2A complex on chromatin. Loss of UBR5 leads to transcriptional rescue of Menin-KMT2A target genes leading to decreased sensitivity to all MIs. Thus, we present UBR5 as an important regulator of Menin/KMT2A complex stability and Menin destabilization/subcellular localization as a designable feature of Menin inhibition targeting KMT2A-r leukemias.
2025-08-01 | GSE299100 | GEO
Project description:Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
| S-EPMC10060155 | biostudies-literature
Project description:UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [ChIP-seq]
| PRJNA1272575 | ENA
Project description:UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [RNA-seq]
| PRJNA1272588 | ENA
Project description:Treatment with Menin inhibitor (MI) disrupts interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, majority of patients with AML with MLLr or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin, or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in cell line or PD AML cell xenografts harboring MLL1r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLLr AML cells expressing FLT3 mutation, also CRISPR edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1r or mtNPM1.
2022-03-12 | GSE190719 | GEO
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:Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.
2024-11-20 | GSE249078 | GEO
Project description:Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.
2024-11-20 | GSE249076 | GEO