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Publication

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

Cancer cell | 2019

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.

Pubmed ID: 31821784 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: U01 CA199000
Agency: NCI NIH HHS, United States
Id: P50 CA206963
Agency: NCI NIH HHS, United States
Id: U01 CA199222
Agency: NCI NIH HHS, United States
Id: R01 CA176745
Agency: NCI NIH HHS, United States
Id: R01 CA204639
Agency: NCI NIH HHS, United States
Id: P01 CA066996

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This is a list of tools and resources that we have found mentioned in this publication.

SAMTOOLS (tool)

RRID:SCR_002105

Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.

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HTSeq (tool)

RRID:SCR_005514

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on February 28,2023. Software Python package that provides infrastructure to process data from high-throughput sequencing assays. While the main purpose of HTSeq is to allow you to write your own analysis scripts, customized to your needs, there are also a couple of stand-alone scripts for common tasks that can be used without any Python knowledge.

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RRID:SCR_006442

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RRID:SCR_009803

Software package for high-performance read alignment, quantification and mutation discovery.General purpose read aligner which can be used to map both genomic DNA-seq reads and RNA-seq reads. Subread aligner as fast, accurate and scalable read mapping by seed-and-vote.These programs were also implemented in Bioconductor R package Rsubread.

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Illumina (tool)

RRID:SCR_010233

American company incorporated that develops, manufactures and markets integrated systems for the analysis of genetic variation and biological function. Provides a line of products and services that serve the sequencing, genotyping and gene expression and proteomics markets. Its headquarters are located in San Diego, California.

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RRID:SCR_010946

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RRID:SCR_013554

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RRID:SCR_016368

Ultrafast and memory efficient tool for aligning sequencing reads to long reference sequences. Supports gapped, local, and paired end alignment modes. More suited to finding longer, gapped alignments in comparison with original Bowtie method.

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bcl2fastq (tool)

RRID:SCR_015058

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DESeq2 (tool)

RRID:SCR_015687

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