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Constitutively activating MEK1 mutations drive treatment refractory histiocytic neoplasms but confer response to ERK inhibition

GSE268618 Mus musculus (mouse) RNA-seq (gene expression) 12 samples Submitted 2024/09/03 Platform GPL34290
At a glance

RNA-seq (gene expression) · mouse · 12 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Mus musculus (mouse)
Samples
12 samples: 12 samples, each with a distinct title — no replicated groupsGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibitionCancer cell · 2026
Summary (written by the submitters)
Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating MAP kinase signaling, including BRAFV600E mutations in ~50% of patients, which confer robust responses to BRAF inhibition. More recently, the MEK inhibitor cobimetinib was FDA-approved for BRAFV600-wild-type histiocytosis patients.
Read the full summary ↓
Here following genomic analysis of 500 pediatric and adult patients with diverse histiocytoses, the most common alteration following BRAFV600E was MEK1E102_I103 in-frame deletion. MEK1E102_I103del and related RAF-independent MEK mutants were associated with an aggressive multi-system clinical phenotype with worse progression-free survival with MEK inhibition as compared to patients with other classes of MEK1/2 mutations. Given that cancer-associated MEK1/2 mutations have not been modeled in vivo and the clinical importance of MEK1 mutations in histiocytoses, we generated MEK1E102_I103del conditional knock-in mice. Using three distinct hematopoietic Cre drivers, these mice developed a 100% penetrant, lethal disorder by 6 weeks of age with expansion of classical and non-classical monocytes, macrophages, and Cd11b+ conventional dendritic cells which infiltrated hematopoietic organs, liver, and skin. MEK1-mutant mice were sensitive to single-agent treatment with the oral ERK inhibitor ulixertinib. We consequently treated five MEK1E102_I103del-mutant patients with ulixertinib on prospective IRB-approved Single Patient Use Expanded Access protocols, four of whom had disease refractory to MEK inhibition. Four of five patients experienced objective clinical and/or radiological responses to ulixertinib. These data reveal the impact of oncogenic MEK kinase mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition as a therapeutic approach to overcome resistance to MEK inhibition in histiocytoses.
Published in
RAF-independent MEK mutations drive refractory histiocytic neoplasms but respond to ERK inhibition
Diamond EL, Emile JF, Fujino T et al. · Cancer cell 2026 · PMID 41135521 · doi:10.1016/j.ccell.2025.09.014
This dataset
Open GSE268618 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE268618_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1117906 and SRA study SRP510680. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41135521) ↗
Study design
12 samples, each with a distinct title — no replicated groups

Supports a case/control comparison: 6 samples read as cases, 6 as controls.

How we read this: Read from 12 sample titles: 12 distinct titles with little repetition. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
Datasets on a similar topic

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