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A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [Cut&Run]

ABSTRACT: CRISPR mediated gene inactivation of MEN1 does not lead to loss of MLL1n chromatin occupancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137814 | GEO | 2019/11/06

REPOSITORIES: GEO

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A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.

Project description:Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.

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A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [RNA-Seq II]

Project description:Using 3-end RNA-seq followed by digital gene expression analyses we assessed genes that change expression upon genetic loss of MEN1 for 6 days in triplicates of samples.

2019-11-06 | GSE137813 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-11-06 | GSE127508 | GEO

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

Project description:Treatment of cells carrying MLL-rearrangements with VTP-50469 (specific Menin-MLL1 inhibitor) displaces Menin from high molecular weight complexes and chromatin genome-wide. Since VTP-50469 block Menin interaction with MLL1 we tested using chip-seq if treatment with VTP-50469 also displaces MLL1 or MLL-fusions from chromatin. We found that the VTP-50469 treatment displaced MLL-fusions from only a subset of MLL-fusion binding sites. Since DOT1L is associated with MLL-AF9 we then tested if displacement of MLL1 also leads to loss of DOT1L association with chromatin on MLL-AF9 binding sites. We found that DOT1L binds to thousands of genes, treatment with VTP-50469 leads to genome wide loss of DOT1L binding including the same subset of MLL-fusion binding sites.

2019-11-06 | GSE127507 | GEO

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

Project description:Cells carrying MLL-rearrangements are sensitive to treatment with VTP-50469 with IC50 in 20-60 nM. We treated MOLM13 or RS4;11 cells with DMSO (0.33%) or VTP-50469 (100-330nM), followed by digital gene expression analyses of 3'end RNA-seq data. We found that very few genes significantly change expression >2-fold after 2 days of treatment, while after 7-day treatment more genes significantly changed expression >2-fold. The genes that lost expression after VTP-50469 treatment were enriched in MLL-fusion target genes and DOT1L-sensitive genes. Moreover, treatment with both EPZ-5676 and VTP-50469 suppress similar subsets of genes, however VTP-50469 suppress genes faster as compared to EPZ-5676. Treatment of PDX with VTP-50469 suppressed similar gene sets, namely MLL-fusion targets and DOT1L-sensitive genes.

2019-11-06 | GSE127506 | GEO

A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [Cut&Run]

Project description:A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [Cut&Run]

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Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia.

Project description:The protein-protein interaction between menin and mixed lineage leukemia 1 (MLL1) plays a critical role in acute leukemias with translocations of the MLL1 gene or with mutations in the nucleophosmin 1 (NPM1) gene. As a step toward clinical translation of menin-MLL1 inhibitors, we report development of MI-3454, a highly potent and orally bioavailable inhibitor of the menin-MLL1 interaction. MI-3454 profoundly inhibited proliferation and induced differentiation in acute leukemia cells and primary patient samples with MLL1 translocations or NPM1 mutations. When applied as a single agent, MI-3454 induced complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia, including patient-derived xenograft models, through downregulation of key genes involved in leukemogenesis. We also identified MEIS1 as a potential pharmacodynamic biomarker of treatment response with MI-3454 in leukemia, and demonstrated that this compound is well tolerated and did not impair normal hematopoiesis in mice. Overall, this study demonstrates, for the first time to our knowledge, profound activity of the menin-MLL1 inhibitor as a single agent in clinically relevant PDX models of leukemia. These data provide a strong rationale for clinical translation of MI-3454 or its analogs for leukemia patients with MLL1 rearrangements or NPM1 mutations.

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

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

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

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

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