Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations [ChIP-Seq]

ABSTRACT: Menin binding to MLL1 is required to maintain self-renewal properties of NPM1c progenitors at different stages of leukemia development

ORGANISM(S): Homo sapiens

PROVIDER: GSE129636 | GEO | 2020/02/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations [RNA-Seq]

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

MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations

Project description:MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations

| PRJNA532379 | ENA

MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations [RNA-Seq]

Project description:MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations [RNA-Seq]

| PRJNA532383 | ENA

MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations [ChIP-Seq]

Project description:MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations [ChIP-Seq]

| PRJNA532384 | ENA

MLL-Menin inhibition reverses pre-leukemic progenitor self-renewal induced by NPM1c mutations

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

2020-02-11 | GSE129638 | GEO

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

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

Multi-omics analysis of MEN1 missense mutations identifies disruption of menin-MLL and menin-JunD interactions as critical requirements for molecular pathogenicity

Project description:Loss-of-function mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are causal to the MEN1 tumor syndrome, but they are also commonly found in sporadic pancreatic neuroendocrine tumors and other types of cancers. The MEN1 gene product, menin, is involved in transcriptional and chromatin regulation, most prominently as an integral component of KMT2A/MLL1 and KMT2B/MLL2 containing COMPASS-like histone H3K4 methyltransferase complexes. In a mutually exclusive fashion, menin also interacts with the JunD subunit of the AP-1 and ATF/CREB transcription factors. After in silico screening of 253 disease-related MEN1 missense mutations, we selected a set of nine menin mutations in surface-exposed residues. The protein interactomes of these mutants were assessed by quantitative mass spectrometry, which indicated that seven of the nine mutants disrupt interactions with both MLL1/2 and JunD complexes in the nucleus. We identified three missense mutations, R52G, E255K and E359K, which display predominant reduction in interaction with MLL1 compared to JunD. This observation was supported by a pronounced loss of binding of the R52G, E255K and E359K mutant proteins at unique MLL1 genomic binding sites with less effect on unique JunD sites. These findings support the general importance of the menin-MLL1 and menin-JunD interactions in MEN1 gene-associated pathogenic conditions.

2022-10-14 | PXD031928 | Pride

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

Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data