Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Oct;37(10):2133-2137.
doi: 10.1038/s41375-023-01965-2. Epub 2023 Jul 19.

Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages

Katherine Sturgess  1   2 , Eliza Yankova  1   2   3 , M S Vijayabaskar  1   2 , Tomoya Isobe  1   2 , Justyna Rak  1   2 , Iwo Kucinski  1   2 , Melania Barile  1   2 , Natalie A Webster  4 , Maria Eleftheriou  1   2   3 , Rebecca Hannah  1   2 , Malgorzata Gozdecka  1   2 , George Vassiliou  1   2 , Oliver Rausch  4 , Nicola K Wilson  1   2 , Berthold Göttgens  5   6 , Konstantinos Tzelepis  7   8   9   10
Affiliations

Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages

Katherine Sturgess et al. Leukemia. 2023 Oct.
No abstract available

PubMed Disclaimer

Conflict of interest statement

NAW and OR are employees of Storm Therapeutics Ltd, Cambridge, UK. KT is a shareholder of and has received research funding from Storm Therapeutics Ltd.

Figures

Fig. 1
Fig. 1. Pharmacological inhibition of METTL3 induces lineage bias in the earliest haematopoietic progenitors.
A RNA-mass spectrometry quantification of in vivo m6A and m62A levels on total RNA using bone marrow from treated mice with vehicle or 50 mg/kg STM2457 (mean ± s.d.,n = 3). P values are indicated as follows: *p < 0.05, **p < 0.01, ***p < 0.005. B Frequency of bone marrow LSK, LSK CD48- CD150+ HSCs (as percentage of lineage-negative cells) and CD48- CD150 + EPCR+ HSCs (as percentage of live cells). Values are shown as individual points with mean and SD. P values were calculated using independent 2-tailed t-test. P values are indicated as follows: *p < 0.05, **p < 0.01, ***p < 0.005. C UMAP representation of the integrated scRNA-seq dataset containing cells from both STM2457 and vehicle-treated LK bone marrow. Clusters are named according to the predominant cell-type present. Contaminating clusters of mature cell-types and clusters containing <2% of the total dataset were not considered in downstream cluster-based analysis and are not included in this representation (50547 cells shown). D Statistically significant cellular abundance changes. P values were calculated using an independent 2-tailed t-test. Cells with Benjamini-Hochberg corrected p values < 0.2 are shown in red if their abundance is increased or blue if depleted in the STM2457-treated bone marrow. LSK lineage negative, Sca1 positive, Kit positive, HSC Haematopoietic stem cell, MPP Multipotent progenitor, MEP Megakaryocyte-erythroid progenitor.
Fig. 2
Fig. 2. Catalytic inhibition of METTL3 in vivo impacts erythroid differentiation and maturation.
A Significant difference in cell fate probability in the MEP cluster (top panel): erythroid (left, adj. p = 1.65e−52) and megakaryocyte probabilities (right, adj p = 2.86e−19). Erythroid probability is significantly reduced in the HSC cluster (bottom panel, left, adj p = 9.55e−86), while neutrophil probability is increased (bottom panel, right, adj p = 3.26e−62). B Differential gene expression dynamics in the neutrophil trajectory. The upper panel shows the density distribution of cell types along pseudotime. The lower panels show gene expression smoothers (line plots) calculated using a generalised additive model for STM2457-treated (red) and vehicle-treated (blue) samples. For p value calculation see materials and methods. C Dynamic changes in cell cycle along the erythroid trajectory from HSCs to late erythroid progenitors. Upper panel shows the density distribution of cells along erythroid pseudotime. Lower panels present the normalized fraction of cells transcriptomically assigned to G1 or S phase along the early erythroid trajectory. Along a given trajectory, the mean fraction of cells that are in a cell cycle phase for each condition was computed. This was performed along a sliding window with a width of 0.01 and step size of 0.0025. More STM2457-treated HSCs, MPPs and MEPs are in G1 phase, and fewer STM2457-treated progenitors are in S-phase. Cells occupying pseudotime earlier than 0.002, representing the earliest progenitors, including LT-HSCs, show no significant difference in cell cycle phase, while pseudotemporally later cells show a separation between STM2457-treated and vehicle-treated, with a trend towards lower S phase and significantly higher G1 phase in the STM2457-treated samples. Mean (coloured line) of STM2457-treated (n = 3) and vehicle-treated (n = 4) samples are shown. The error bars indicate the standard deviation of the fraction of cells across the experiments within a condition. The coloured bar aligned with the x-axis denotes significant differences between STM2457 and vehicle-treated cells (adjusted p < 0.05 orange, adjusted p > 0.05 grey). P values were calculated using a two-tailed t-test with BH correction. D Differential gene expression dynamics in erythroid trajectory (see B for method).
See this image and copyright information in PMC

References

    1. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6. doi: 10.1038/nature11112. - DOI - PubMed
    1. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons. Cell. 2012;149:1635–46. doi: 10.1016/j.cell.2012.05.003. - DOI - PMC - PubMed
    1. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93–5. doi: 10.1038/nchembio.1432. - DOI - PMC - PubMed
    1. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20. doi: 10.1038/nature12730. - DOI - PMC - PubMed
    1. Yankova E, Blackaby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga G, et al. Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 2021. Accessed 5 May 2021. http://www.nature.com/articles/s41586-021-03536-w - PMC - PubMed

Publication types

LinkOut - more resources