GEO series

DOT1L controls NK cell maturation and lineage integrity [RNA-seq D0 & D2]

GSE222233 Mus musculus (mouse) RNA-seq (gene expression) 11 samples Submitted 2024/04/30 Platform GPL30215

At a glance

RNA-seq (gene expression) · mouse · 11 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: 11 samples: 3 × splenic sorted NK cells, wild type, vs 3 × splenic sorted NK cells, knockout, vs 3 × splenic sorted NK cells, knockout, d2 MCMV, vs 2 × splenic sorted NK cells, wild type, d2 MCMV,Groups 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: DOT1L maintains NK cell phenotype and function for optimal tumor controlCell reports · 2024

Summary (written by the submitters)

Epigenetic modifiers are promising targets to improve therapies in patients with cancer. Targeting the methyltransferase DOT1L with small molecule inhibitors has shown promising effects on the control of cancerous cells. However, these small molecules are given systemically and may have a profound impact on non-cancerous cells, such as the cells of the immune system.

Read the full summary ↓

In the innate immune system, natural killer (NK) cells are a critical subset of cells with important roles in controlling transformed cells and tumour inflammation. Previous studies have shown that NK cells can convert into ILC1-like cells in a TGFβ-rich tumour microenvironment (TME). Additionally, cancer patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) have increased frequencies of ILC1 cells in peripheral blood mononuclear cells (PBMCs), which show reduced production of proinflammatory cytokines and decreased granzyme B production. In this study, we identify DOT1L as a critical regulator of NK cell activation and lineage integrity. We generated NKp46-conditional DOT1L knockout mice (DOT1L.Ncr1) and observed increased frequencies of ILC1-like cells (CD49b+ CD49a+, CD62L-) and reduced frequencies of NK cells (CD49b+ CD49a-, CD62L+) in these mice. While the absence of DOT1L increases the sensitivity to TGFβ, the increased expression of CD49a is highly intrinsic and only partially dependent on TGFβ signalling. Functionally, the increased presence of ILC1-like cells in the tumour microenvironment of DOT1L.Ncr1 mice leads to decreased tumour control. Our assessment of the transcriptional program reveals alternative uses of transcription factors, such as the AP-1 family or SMAD2/3, to maintain NK cell activation and lineage integrity. Our findings provide evidence for a previously unknown role of DOT1L in NK cell biology, and demonstrate the importance of maintaining NK cell lineage integrity for effective tumour control. These findings have significant implications for the development of improved therapies for cancer or other NK cell-lineage dependent malignancies.

Published in

DOT1L maintains NK cell phenotype and function for optimal tumor control

Sudholz H, Schuster IS, Foroutan M et al. · Cell reports 2024 · PMID 38865244 · doi:10.1016/j.celrep.2024.114333

This dataset

Open GSE222233 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 GSE222233_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 PRJNA918656 and SRA study SRP415998. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38865244) ↗

Study design

3 × splenic sorted NK cells, wild type, vs 3 × splenic sorted NK cells, knockout, vs 3 × splenic sorted NK cells, knockout, d2 MCMV, vs 2 × splenic sorted NK cells, wild type, d2 MCMV,

Supports a case/control comparison: 6 samples read as cases, 5 as controls.

How we read this: 4 replicated groups read from 11 sample titles; they account for 11 of them. 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

GSM6918474 splenic sorted NK cells, wild type, rep1 splenic sorted NK cells…
GSM6918475 splenic sorted NK cells, wild type, rep2 splenic sorted NK cells…
GSM6918476 splenic sorted NK cells, wild type, rep3 splenic sorted NK cells…
GSM6918477 splenic sorted NK cells, knockout, rep1 splenic sorted NK cells…
GSM6918478 splenic sorted NK cells, knockout, rep2 splenic sorted NK cells…
GSM6918479 splenic sorted NK cells, knockout, rep3 splenic sorted NK cells…
GSM6918480 splenic sorted NK cells, wild type, d2 MCMV, rep1 splenic sorted NK cells…
GSM6918481 splenic sorted NK cells, wild type, d2 MCMV, rep2 splenic sorted NK cells…
GSM6918482 splenic sorted NK cells, knockout, d2 MCMV, rep1 splenic sorted NK cells…
GSM6918483 splenic sorted NK cells, knockout, d2 MCMV, rep2 splenic sorted NK cells…
GSM6918484 splenic sorted NK cells, knockout, d2 MCMV, rep3 splenic sorted NK cells…

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