Mezigdomide is effective alone and in combination with Menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML
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ABSTRACT:
PROVIDER: PRJNA970400 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24474442_1.fastq.gz | Fastqsanger.gz | |||
| SRR24474442_2.fastq.gz | Fastqsanger.gz | |||
| SRR24474443_1.fastq.gz | Fastqsanger.gz | |||
| SRR24474443_2.fastq.gz | Fastqsanger.gz | |||
| SRR24474444_1.fastq.gz | Fastqsanger.gz |
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Project description:Small molecules that target the MENIN-KMT2A protein-protein interaction (Menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A, MLL1) rearranged (KMT2A-r) and nucleophosmin mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with Lenalidomide or Iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. Recently, the novel IKAROS degrader Mezigdomide was developed and has greatly enhanced IKAROS protein degradation. In this study we show that Mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to Lenalidomide and Iberdomide. Further, we demonstrate that Mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with Menin inhibitors. We show that the superior activity of Mezigdomide compared to Lenalidomide or Iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent Mezigdomide was efficacious in five patient derived xenograft (PDX) models of KMT2A-r and one NPM1c AML. The combination of Mezigdomide with a Menin inhibitor increased survival and prevented the development of recently described MEN1 mutations. These results support prioritization of Mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.
2024-02-15 | PXD041735 | Pride
Project description:Small molecules that target the MENIN-KMT2A protein-protein interaction (Menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A, MLL1) rearranged (KMT2A-r) and nucleophosmin mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with Lenalidomide or Iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. Recently, the novel IKAROS degrader Mezigdomide was developed and has greatly enhanced IKAROS protein degradation. In this study we show that Mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to Lenalidomide and Iberdomide. Further, we demonstrate that Mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with Menin inhibitors. We show that the superior activity of Mezigdomide compared to Lenalidomide or Iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent Mezigdomide was efficacious in five patient derived xenograft (PDX) models of KMT2A-r and one NPM1c AML. The combination of Mezigdomide with a Menin inhibitor increased survival and prevented the development of recently described MEN1 mutations. These results support prioritization of Mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.
2024-02-15 | PXD041737 | Pride
Project description:To compare gene expression changes following treatment with two CELMoDs (cereblon E3 ligase modulators) in a Lysine Methyltransferase 2A-rearranged (KMT2A-r) acute myeloid leukemia cell line, we compared gene expression changes after 72 hour of treatment with Iberdomide/CC-220 and Mezigdomide/CC-92480.
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Project description:Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and is frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole genome CRISPR/Cas9 screens, we identify specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin- KMT2A/B complexes in maintaining bivalency. Unexpectedly, genetic loss or pharmacological inhibition of Menin phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. Whilst Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals novel therapeutic opportunities that can be leveraged through inhibition of Menin.
2023-01-13 | GSE222516 | GEO
Project description:Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)
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Project description:Menin binding to MLL1 is required to maintain self-renewal properties of NPM1c progenitors at different stages of leukemia development
2020-02-11 | GSE129637 | GEO
Project description:Menin binding to MLL1 is required to maintain self-renewal properties of NPM1c progenitors at different stages of leukemia development
2020-02-11 | GSE129636 | GEO
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: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