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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60673 | GEO | 2017/08/21

SECONDARY ACCESSION(S): PRJNA259220

REPOSITORIES: GEO

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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

Gene expression induced by DOT1L and Menin inhibition in cell line models of leukemia

Project description:Gene expression upon DOT1L inhibition, or Menin inhibition, or a combination of DOT1L and Menin inhibiting agents, was assessed in several MLL-rearranged human cell lines and a mouse model of MLL-AF9 leukemia. The goal of the study was to explore the mechanisms by which the EPZ0004777 and MI-2-2 chemicals collaborate to induce differentiation and cell death in MLL-AF4 and MLL-AF9 leukemias.

2016-11-14 | GSE63664 | GEO

Transcriptome profiling of HepG2 cells upon treatment of the menin-MLL inhibitor MI-503 or DMSO

Project description:Hepatocellular carcinoma (HCC) accounts for the majority of malignant liver tumors and results in many deaths each year, emphasizing the need for new therapies. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients. Therefore, we performed RNA sequencing experiment to determine the transcriptome change in the HepG2 cells upon treatment of MI-503, a small molecule inhibitor of the menin-MLL1 interaction with optimized drug-like properties

2018-02-16 | GSE103327 | GEO

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

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

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [RNA-seq]

Project description:The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. Here, we delineate a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that Menin safeguards leukemia cell fitness by impeding binding of the histone demethylase UTX at a subset of non-canonical target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of genes with tumor suppressive function. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are accompanied by induction of tumor suppressive gene expression at Menin-UTX targets. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.

2022-11-16 | GSE186709 | GEO

A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition [ChIP-seq]

2022-11-16 | GSE186695 | GEO

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

2015-03-02 | GSE60836 | GEO

Assesment of gene expression upon AF10 deletion in MLL-AF9 secondary leukemia

Project description:Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Primary MLL-AF9 leukemias in the AF10 floxed background (homozygous) were transduced with MSCV-IRES-tdTomato (MIT) or the Cre recombinase expressing MIT vector, cells were sorted and injected into secondary recipient mice to generate Af10 floxed (MIT) or deleted (CRE) leukemias. BM cells fresly harvested from these leukemias were sorted for tdTomato expression and used for microarrays. BM cells from Hoxa9-Meis1 transduced primary leukemias were used for comparison.

2014-09-08 | E-GEOD-54499 | biostudies-arrayexpress

Menin-MLL inhibitors block oncogenic transformation by MLL fusion proteins in a fusion partner independent manner

Project description:Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL) gene result in fusion proteins which retain the N-terminal portion of MLL fused with one of more than 70 different fusion partners. The high diversity of MLL fusion partners raises a question whether it is possible to develop a general therapeutic strategy to block the oncogenic activity of MLL fusion proteins in a fusion partner independent manner. We have demonstrated that blocking the menin-MLL interaction using small molecule inhibitor inhibits oncogenic activity of different MLL fusion proteins according to a mechanism that is independent on the fusion partner.

2018-06-09 | GSE69740 | GEO

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