CoChat
Sign Up
Cited by 14

The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.

TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling

Yang, Yitong, Cathelin, Severine, Liu, Alex C. H., Subedi, Amit, Maher, Abdula, Hosseini, Mohsen, Manikoth Ayyathan, Dhanoop, Vanner, Robert, Chan, Steven M.·2025·Nature Communications
DOI 10.1038/s41467-025-57614-yPMC PMC11894142

Published version of a preprint

Open this paper in CoChat — free account

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-025-57614-y

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Tet2KO HSPCs are dependent on DOT1L activity. A Percentage of BFP−Tet2WT or BFP−Tet2KO HPCHOXB4 cells in competition with BFP+Tet2WT HPCHOXB4 cells at the indicated time points after starting the experiment. n = 3 experimental replicates. Unpaired t test used for significance. B The percentage of BFP−Tet2KO HPCHOXB4 cells after treatment with the indicated compounds or DMSO (highlighted in orange) for 14 days. The dashed line represents the percentage of Tet2KO HPCHOXB4 in DMSO treatment. Data represent the average of 3 experimental replicates. Representative data from one of 3 independent screens are shown. C Count of Annexin V negative Tet2KO or Tet2WT HPCHOXB4 cells treated with 1 μM of each compound over time normalized to the corresponding untreated sample. n = 3 experimental replicates. Unpaired t test with multiple testing corrections used for significance. D Percentage of Venus+Tet2WT or Venus+Tet2KO HPCHOXB4 cells in competition with Venus−Tet2WT HPCHOXB4 cells over time. Both cell types were transduced with the indicated shRNA vectors. n = 3 experimental replicates. Unpaired t test used for significance. E Proportion of CD45.2+Tet2KO or CD45.2+Tet2WT HSPCs in competition with CD45.1+Tet2WT HSPCs after treatment with DMSO or SGC0946 (SGC; 1 μM). Data are normalized to DMSO-treated CD45.2+Tet2WT cells. Unpaired t test used for significance. n = 3 experimental replicates. F Proportion of CD45.2+Tet2KO or CD45.2+Tet2WT HSPCs in competition with CD45.1+Tet2WT HSPCs gated on the transduced BFP+ population. Data are normalized to shNT-expressing CD45.2+Tet2WT cells. Unpaired t test used for significance. n = 3 experimental replicates. Data are shown as mean ± SEM. G Number of colonies formed in per 1 × 104 Lin-Kit+ (LK) HSPCs in the presence of DMSO or SGC0946 (SGC; 1 μM). n = 3 experimental replicates. Unpaired t test used for significance. All data shown are mean ± SD unless otherwise indicated. Asterisks indicate statistical significance. Source data are provided as a Source Data file.
Fig. 1 Tet2KO HSPCs are dependent on DOT1L activity. A Percentage of BFP−Tet2WT or BFP−Tet2KO HPCHOXB4 cells in competition with BFP+Tet2WT HPCHOXB4 cells at the indicated time points after starting the experiment. n = 3 experimental replicates. Unpaired t test used for significance. B The percentage of BFP−Tet2KO HPCHOXB4 cells after treatment with the indicated compounds or DMSO (highlighted in orange) for 14 days. The dashed line represents the percentage of Tet2KO HPCHOXB4 in DMSO treatment. Data represent the average of 3 experimental replicates. Representative data from one of 3 independent screens are shown. C Count of Annexin V negative Tet2KO or Tet2WT HPCHOXB4 cells treated with 1 μM of each compound over time normalized to the corresponding untreated sample. n = 3 experimental replicates. Unpaired t test with multiple testing corrections used for significance. D Percentage of Venus+Tet2WT or Venus+Tet2KO HPCHOXB4 cells in competition with Venus−Tet2WT HPCHOXB4 cells over time. Both cell types were transduced with the indicated shRNA vectors. n = 3 experimental replicates. Unpaired t test used for significance. E Proportion of CD45.2+Tet2KO or CD45.2+Tet2WT HSPCs in competition with CD45.1+Tet2WT HSPCs after treatment with DMSO or SGC0946 (SGC; 1 μM). Data are normalized to DMSO-treated CD45.2+Tet2WT cells. Unpaired t test used for significance. n = 3 experimental replicates. F Proportion of CD45.2+Tet2KO or CD45.2+Tet2WT HSPCs in competition with CD45.1+Tet2WT HSPCs gated on the transduced BFP+ population. Data are normalized to shNT-expressing CD45.2+Tet2WT cells. Unpaired t test used for significance. n = 3 experimental replicates. Data are shown as mean ± SEM. G Number of colonies formed in per 1 × 104 Lin-Kit+ (LK) HSPCs in the presence of DMSO or SGC0946 (SGC; 1 μM). n = 3 experimental replicates. Unpaired t test used for significance. All data shown are mean ± SD unless otherwise indicated. Asterisks indicate statistical significance. Source data are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 2 Mpl expression is upregulated and associated with increased H3K79me2 at the gene locus in Tet2KO HSPCs. A Volcano plots of differentially expressed genes (DEGs) comparing Tet2KO versus Tet2WT HPCHOXB4 cells and SGC0946-treated versus untreated Tet2WT HPCHOXB4 cells. B Venn diagram showing the overlap of DEGs upregulated in Tet2KO cells and downregulated in SGC0946-treated Tet2KO cells. C Heatmap showing the z-scaled normalized read counts of the 20 overlapping genes in (B). D Distribution of H3K79me2 signals at the transcription start site (TSS) and gene body. Each curve represents data randomly sampled from two replicates in the same group. E Distribution of H3K79me2 signals centered around the TSS of differentially methylated genes of each indicated pairwise comparison. The values in each row represent data randomly sampled from two replicates. F Venn diagram showing the overlap between the 4 sets of genes defined by differential gene expression and H3K79me2 levels. G Mpl gene expression by RT-qPCR in HPCHOXB4 cells and unmodified Lin-Kit+ HSPCs treated either with DMSO (DM) or SGC0946 (SGC, 1 μM) for 7 days. Ct values were normalized to Actb. Expression was shown as FC normalized to Tet2WT. n = 3 experimental replicates. Unpaired t test used for significance. H Genome browser view of H3K79me2 signals at the Mpl locus in HPCHOXB4 cells (n = 2 biological replicates). Data shown are mean ± SD. Asterisks indicate statistical significance. Source data are provided as a Source Data file.
Fig. 2 Mpl expression is upregulated and associated with increased H3K79me2 at the gene locus in Tet2KO HSPCs. A Volcano plots of differentially expressed genes (DEGs) comparing Tet2KO versus Tet2WT HPCHOXB4 cells and SGC0946-treated versus untreated Tet2WT HPCHOXB4 cells. B Venn diagram showing the overlap of DEGs upregulated in Tet2KO cells and downregulated in SGC0946-treated Tet2KO cells. C Heatmap showing the z-scaled normalized read counts of the 20 overlapping genes in (B). D Distribution of H3K79me2 signals at the transcription start site (TSS) and gene body. Each curve represents data randomly sampled from two replicates in the same group. E Distribution of H3K79me2 signals centered around the TSS of differentially methylated genes of each indicated pairwise comparison. The values in each row represent data randomly sampled from two replicates. F Venn diagram showing the overlap between the 4 sets of genes defined by differential gene expression and H3K79me2 levels. G Mpl gene expression by RT-qPCR in HPCHOXB4 cells and unmodified Lin-Kit+ HSPCs treated either with DMSO (DM) or SGC0946 (SGC, 1 μM) for 7 days. Ct values were normalized to Actb. Expression was shown as FC normalized to Tet2WT. n = 3 experimental replicates. Unpaired t test used for significance. H Genome browser view of H3K79me2 signals at the Mpl locus in HPCHOXB4 cells (n = 2 biological replicates). Data shown are mean ± SD. Asterisks indicate statistical significance. Source data are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 3 DOT1L enhances self-renewal of Tet2KO HSCs through differentially regulating Mpl expression. A Schematic diagram of scRNA-seq on Tet2WT and Tet2KO Lin-Kit+ HSPCs. Created in BioRender84. B Dimensionality reduction using Uniform Manifold Approximation and Projection (UMAP) on all the filtered cells (n = 68,538). C Proportion of progenitor lineages of each genotype and treatment group averaged from two biological replicates. VEH: vehicle. PINO: pinometostat. D Proportion of individual HSC clusters normalized to the total cell number in each sample. Data shown are mean ± SD. Significance levels shown represent two-sided Fisher’s exact test results using the sum of raw counts from two biological replicates. E Scatterplot of cells with detected Mpl transcripts (red) and cells with no Mpl detected (gray) grouped by genotype and treatment. Two biological replicates were merged. F Percent of cells with detected Mpl transcripts in vehicle-treated samples grouped by genotype. G Percent of Mpl-high HSCs among all HSCs of each group. p values were calculated through two-sided Fisher’s exact test using the sum of two replicates. Raw counts are shown in table S3F. H AUC enrichment score of Mpl-expressing (Mpl+) and non-expressing (Mpl-) vehicle-treated HSCs from HSC-1 for each gene set. The lower and upper hinges of the box represent the 25th and 75th percentiles, and the whiskers extend to the minimum and maximum values within 1.5 times the interquartile range. The median value is depicted by the line within the box. n = 532 for Tet2WTMpl+; n = 1,855 for Tet2WTMpl-; n = 1,184 for Tet2KOMpl+; n = 2574 for Tet2KOMpl-. Unpaired t test used for significance. I Heatmap showing normalized expression of differentially expressed ( | Log2FC > 1 | , padj <0.01) HSC and progenitor markers in HSCs from HSC-1 cluster grouped by Mpl status and genotype. J Percentage of each stem and progenitor fraction in CD45.2+ LSK BM from primary recipients at the endpoint. n = 5 biological replicates per group. Data shown are mean ± SD. Unpaired t test with multiple testing correction using Holm–Sidak method used for significance. K Percentage of CD45.2+ BM cells in each stem and progenitor population in secondary transplant recipients three weeks following transplantation. Data shown are mean ± SD. n = 5 biological replicates per group. Unpaired t test used for significance. Asterisks indicate statistical significance. Source data are provided as a Source Data file.
Fig. 3 DOT1L enhances self-renewal of Tet2KO HSCs through differentially regulating Mpl expression. A Schematic diagram of scRNA-seq on Tet2WT and Tet2KO Lin-Kit+ HSPCs. Created in BioRender84. B Dimensionality reduction using Uniform Manifold Approximation and Projection (UMAP) on all the filtered cells (n = 68,538). C Proportion of progenitor lineages of each genotype and treatment group averaged from two biological replicates. VEH: vehicle. PINO: pinometostat. D Proportion of individual HSC clusters normalized to the total cell number in each sample. Data shown are mean ± SD. Significance levels shown represent two-sided Fisher’s exact test results using the sum of raw counts from two biological replicates. E Scatterplot of cells with detected Mpl transcripts (red) and cells with no Mpl detected (gray) grouped by genotype and treatment. Two biological replicates were merged. F Percent of cells with detected Mpl transcripts in vehicle-treated samples grouped by genotype. G Percent of Mpl-high HSCs among all HSCs of each group. p values were calculated through two-sided Fisher’s exact test using the sum of two replicates. Raw counts are shown in table S3F. H AUC enrichment score of Mpl-expressing (Mpl+) and non-expressing (Mpl-) vehicle-treated HSCs from HSC-1 for each gene set. The lower and upper hinges of the box represent the 25th and 75th percentiles, and the whiskers extend to the minimum and maximum values within 1.5 times the interquartile range. The median value is depicted by the line within the box. n = 532 for Tet2WTMpl+; n = 1,855 for Tet2WTMpl-; n = 1,184 for Tet2KOMpl+; n = 2574 for Tet2KOMpl-. Unpaired t test used for significance. I Heatmap showing normalized expression of differentially expressed ( | Log2FC > 1 | , padj <0.01) HSC and progenitor markers in HSCs from HSC-1 cluster grouped by Mpl status and genotype. J Percentage of each stem and progenitor fraction in CD45.2+ LSK BM from primary recipients at the endpoint. n = 5 biological replicates per group. Data shown are mean ± SD. Unpaired t test with multiple testing correction using Holm–Sidak method used for significance. K Percentage of CD45.2+ BM cells in each stem and progenitor population in secondary transplant recipients three weeks following transplantation. Data shown are mean ± SD. n = 5 biological replicates per group. Unpaired t test used for significance. Asterisks indicate statistical significance. Source data are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 4 Inhibition of the TPO-R/JAK/STAT signaling axis suppresses clonal expansion of Tet2KO mouse and human HSPCs. A Percentage of BFP+ CD45.2+Tet2KO or Tet2WT BM in competition with CD45.1+Tet2WT cells at day 6 of plating. Data shown are mean ± SD. Unpaired t test used for significance. n = 3 experimental replicates. B Schematic diagram of the in vivo competition experiment evaluating the effect of Mpl knockdown on the competitive advantage of Tet2KO HSPCs. Created in BioRender85. C Change in the percentage of CD45.2+Tet2KO cells in BFP+ peripheral blood cells from baseline to 17 weeks after doxycycline administration. n = 4 for shNT and n = 7 for shMpl. Data are shown as mean ± SEM. Unpaired t test used for significance. D Percentage of HSCs in transduced LK BM of Tet2WT (CD45.1) or Tet2KO cells at the endpoint. Data are shown as mean ± SEM. Unpaired t test used for significance. E Percentage of CD45.2+Tet2WT or CD45.2+Tet2KO HSPCs in competition with CD45.1+Tet2WT HSPCs after treatment with DMSO or ruxolitinib (1 μM) for 6 days. Data are shown as mean ± SD. Unpaired t test used for significance. n = 3 experimental replicates. F Number of colonies in media supplemented with DMSO (0.01%) or ruxolitinib (RUX, 1 μM). Data are shown as mean ± SD. Unpaired t test used for significance. n = 3 experimental replicates. G Western blot showing phosphorylated STAT5 (pSTAT5) levels in Tet2WT (WT) and Tet2KO (KO) LK BM with (+) or without (-) TPO stimulation. H AUC enrichment scores of LK BM cells from each genotype and treatment group for STAT5 target gene sets. The lower and upper hinges of the box represent the 25th and 75th percentiles, and the whiskers extend to the minimum and maximum values within 1.5 times the interquartile range. The median value is depicted by the line within the box. Unpaired t test used for significance. I Schematic diagram of the in vivo competition experiment evaluating the effect of ruxolitinib treatment on the competitive advantage of Tet2KO HSPCs. Created in BioRender86. J Percentage of CD45.2+Tet2KO cells in peripheral blood from baseline to the indicated time points. n = 7 per treatment group. Data are shown as mean ± SEM. Unpaired t test used for significance. K Percentage of CD45.2+Tet2KO cells in peripheral blood samples at the endpoint. Data are shown as mean ± SEM. Unpaired t test used for significance. Asterisks indicate statistical significance. Source data are provided as a Source Data file.
Fig. 4 Inhibition of the TPO-R/JAK/STAT signaling axis suppresses clonal expansion of Tet2KO mouse and human HSPCs. A Percentage of BFP+ CD45.2+Tet2KO or Tet2WT BM in competition with CD45.1+Tet2WT cells at day 6 of plating. Data shown are mean ± SD. Unpaired t test used for significance. n = 3 experimental replicates. B Schematic diagram of the in vivo competition experiment evaluating the effect of Mpl knockdown on the competitive advantage of Tet2KO HSPCs. Created in BioRender85. C Change in the percentage of CD45.2+Tet2KO cells in BFP+ peripheral blood cells from baseline to 17 weeks after doxycycline administration. n = 4 for shNT and n = 7 for shMpl. Data are shown as mean ± SEM. Unpaired t test used for significance. D Percentage of HSCs in transduced LK BM of Tet2WT (CD45.1) or Tet2KO cells at the endpoint. Data are shown as mean ± SEM. Unpaired t test used for significance. E Percentage of CD45.2+Tet2WT or CD45.2+Tet2KO HSPCs in competition with CD45.1+Tet2WT HSPCs after treatment with DMSO or ruxolitinib (1 μM) for 6 days. Data are shown as mean ± SD. Unpaired t test used for significance. n = 3 experimental replicates. F Number of colonies in media supplemented with DMSO (0.01%) or ruxolitinib (RUX, 1 μM). Data are shown as mean ± SD. Unpaired t test used for significance. n = 3 experimental replicates. G Western blot showing phosphorylated STAT5 (pSTAT5) levels in Tet2WT (WT) and Tet2KO (KO) LK BM with (+) or without (-) TPO stimulation. H AUC enrichment scores of LK BM cells from each genotype and treatment group for STAT5 target gene sets. The lower and upper hinges of the box represent the 25th and 75th percentiles, and the whiskers extend to the minimum and maximum values within 1.5 times the interquartile range. The median value is depicted by the line within the box. Unpaired t test used for significance. I Schematic diagram of the in vivo competition experiment evaluating the effect of ruxolitinib treatment on the competitive advantage of Tet2KO HSPCs. Created in BioRender86. J Percentage of CD45.2+Tet2KO cells in peripheral blood from baseline to the indicated time points. n = 7 per treatment group. Data are shown as mean ± SEM. Unpaired t test used for significance. K Percentage of CD45.2+Tet2KO cells in peripheral blood samples at the endpoint. Data are shown as mean ± SEM. Unpaired t test used for significance. Asterisks indicate statistical significance. Source data are provided as a Source Data file.CC BY-NC-ND · PubMed Central
Fig. 5 DOT1L inhibition suppresses human TET2 mutated CHIP. A Number of colonies formed per 1 × 104 CD34+ cells with Cas9-mediated knockout in OR2W5P or TET2 (KO-S or KO-D) in methylcellulose containing DMSO, SGC0946 (SGC) at 1 μM, or ruxolitinib (RUX) at 0.5 μM. Unpaired t test used for significance. B Median fluorescent intensity (MFI) of TPO-R staining minus MFI of isotype control staining on CD34+CD38- cord blood cells at 9 days after nucleofection with Cas9 RNPs targeting OR2W5P or TET2. Cells were treated with DMSO or SGC0946 for 7 days prior to analysis. Unpaired t test used for significance. C Variant allele frequency (VAF) of TET2 mutations in HSPCs enriched from mPB samples cultured in different TPO concentrations for the indicated number of days. Unpaired t test used for significance. D VAF of TET2 mutations in HSPCs from mPB samples cultured with DMSO, SGC0946 at 1 μM, or ruxolitinib at 0.5 μM on day 1 and 14 (n = 3). Unpaired t test used for significance. Data shown are mean ± SD unless otherwise indicated. Asterisks indicate statistical significance. Source data are provided as a Source Data file.
Fig. 5 DOT1L inhibition suppresses human TET2 mutated CHIP. A Number of colonies formed per 1 × 104 CD34+ cells with Cas9-mediated knockout in OR2W5P or TET2 (KO-S or KO-D) in methylcellulose containing DMSO, SGC0946 (SGC) at 1 μM, or ruxolitinib (RUX) at 0.5 μM. Unpaired t test used for significance. B Median fluorescent intensity (MFI) of TPO-R staining minus MFI of isotype control staining on CD34+CD38- cord blood cells at 9 days after nucleofection with Cas9 RNPs targeting OR2W5P or TET2. Cells were treated with DMSO or SGC0946 for 7 days prior to analysis. Unpaired t test used for significance. C Variant allele frequency (VAF) of TET2 mutations in HSPCs enriched from mPB samples cultured in different TPO concentrations for the indicated number of days. Unpaired t test used for significance. D VAF of TET2 mutations in HSPCs from mPB samples cultured with DMSO, SGC0946 at 1 μM, or ruxolitinib at 0.5 μM on day 1 and 14 (n = 3). Unpaired t test used for significance. Data shown are mean ± SD unless otherwise indicated. Asterisks indicate statistical significance. Source data are provided as a Source Data file.CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 8 references

Research works printed but not linked: 71

  1. Steensma, D. P. et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndrome. Blood. https://doi.org/10.1182/blood-2015-03-631747 (2015). · DOI · Paper page
  2. Marnell, C. S., Bick, A. & Natarajan, P. Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease. J. Mol. Cell Cardiol. https://doi.org/10.1016/j.yjmcc.2021.07.004 (2021). · DOI
  3. Libby, P. et al. Clonal hematopoiesis: Crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. J. Am. Coll. Cardiol. 74, 567–577 (2019). · DOI
  4. Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES cell self-renewal, and ICM specification. Nature 466, 1129 (2010). · DOI · Paper page
  5. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017). · DOI · Paper page
  6. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Eng. J Med. https://doi.org/10.1056/nejmoa1409405 (2014). · DOI · Paper page
  7. Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. https://doi.org/10.1038/nm.3733 (2014). · DOI · Paper page
  8. Buscarlet, M. et al. Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A. Blood 132, 277–280 (2018). · DOI · Paper page
  9. He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. https://doi.org/10.1126/science.1210944 (2011). · DOI
  10. Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. https://doi.org/10.1126/science.1210597 (2011). · DOI · Paper page
  11. Quivoron, C. et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20, 25–38 (2011). · DOI · Paper page
  12. Kunimoto, H. et al. Tet2 disruption leads to enhanced self-renewal and altered differentiation of fetal liver hematopoietic stem cells. Sci. Rep. 2, 1–10 (2012). · DOI
  13. Ko, M. et al. Ten-eleven-translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc. Natl Acad. Sci. USA 108, 14566–14571 (2011). · DOI · Paper page
  14. Sauvageau, G. et al. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev. 9, 1753–1765 (1995). · DOI
  15. Cusan, M. et al. Controlled stem cell amplification by HOXB4 depends on its unique proline-rich region near the N terminus. Blood. https://doi.org/10.1182/blood-2016-04-706978 (2017). · DOI
  16. Schiroli, G. et al. Cell of origin epigenetic priming determines susceptibility to Tet2 mutation. Nat. Commun. https://doi.org/10.1038/S41467-024-48508-6 (2024). · DOI
  17. Huerga Encabo, H. et al. Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils. Cell Stem Cell 30, 781–799.e9 (2023). · DOI · Paper page
  18. Ackloo, S., Brown, P. J. & Müller, S. Chemical probes targeting epigenetic proteins: Applications beyond oncology. Epigenetics 12, 378–400 (2017). · DOI
  19. Yu, W. et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3, 1288 (2012). · DOI
  20. Stein, E. M. et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. https://doi.org/10.1182/blood-2017-12-818948 (2018). · DOI · Paper page
  21. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010). · DOI · Paper page
  22. Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011). · DOI
  23. Cobo, I. et al. DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages. Immunity 55, 1386–1401.e10 (2022). · DOI
  24. Koepp, D. M., Harper, J. W. & Elledge, S. J. How the cyclin became a cyclin: regulated proteolysis in. Cell cycle Cell 97, 431–434 (1999).
  25. Yokoyama, S., Takada, K., Hirasawa, M., Perera, L. P. & Hiroi, T. Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease. J. Clin. Immunol. 31, 1038–1044 (2011). · DOI
  26. Tanaka, T., Narazaki, M. & Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/CSHPERSPECT.A016295 (2014). · DOI · Paper page
  27. Nguyen, A. T. & Zhang, Y. The diverse functions of Dot1 and H3K79 methylation. Genes Dev. 25, 1345–1358 (2011). · DOI
  28. Vigon, I. et al. Molecular cloning and characterization of MPL, the human homolog of the v- mpl oncogene: Identification of a member of the hematopoietic growth factor receptor superfamily. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.89.12.5640 (1992). · DOI
  29. Skoda, R. C. et al. Murine c-mpl: A member of the hematopoietic growth factor receptor superfamily that transduces a proliferative signal. EMBO J. https://doi.org/10.1002/j.1460-2075.1993.tb05925.x (1993). · DOI
  30. Takashima, S. et al. Molecular cloning and expression of a sixth type of alpha 2,8-sialyltransferase (ST8Sia VI) that sialylates O-glycans. J. Biol. Chem. 277, 24030–24038 (2002). · DOI
  31. Sitnicka, E. et al. The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood 87, 4998–5005 (1996). · DOI
  32. Yagi, M. et al. Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proc. Natl Acad. Sci. USA 96, 8126–8131 (1999). · DOI
  33. Fox, N., Priestley, G., Papayannopoulou, T. & Kaushansky, K. Thrombopoietin expands hematopoietic stem cells after transplantation. J. Clin. Invest 110, 389–394 (2002). · DOI
  34. Cano-Rodriguez, D. et al. Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner. Nat. Commun. 7, 12284 (2016). · DOI
  35. Katayamaa, N. et al. Role for C-MPL and its ligand thrombopoietin in early hematopoiesis. Leuk. Lymphoma 28, 51–56 (1997). · DOI
  36. Yoshihara, H. et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1, 685–697 (2007). · DOI
  37. Waters, N. J. et al. Exploring drug delivery for the DOT1L inhibitor pinometostat (EPZ-5676): Subcutaneous administration as an alternative to continuous IV infusion, in the pursuit of an epigenetic target. J. Controlled Release 220, 758–765 (2015). · DOI
  38. Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015). · DOI · Paper page
  39. Paul, F. et al. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163, 1663–1677 (2015). · DOI · Paper page
  40. Xie, J. et al. STING activation in TET2-mutated hematopoietic stem/progenitor cells contributes to the increased self-renewal and neoplastic transformation. Leukemia 37, 2457–2467 (2023). · DOI
  41. Li, Z. et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118, 4509 (2011). · DOI · Paper page
  42. Graham, S. M., Vass, J. K., Holyoake, T. L. & Graham, G. J. Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells 25, 3111–3120 (2007). · DOI
  43. Park, I. K. et al. Differential gene expression profiling of adult murine hematopoietic stem cells. Blood 99, 488–498 (2002). · DOI
  44. Kimura, S., Roberts, A. W., Metcalf, D. & Alexander, W. S. Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. Proc. Natl Acad. Sci. 95, 1195–1200 (1998). · DOI
  45. Solar, G. P. et al. Role of c-mpl in early hematopoiesis. Blood 92, 4–10 (1998). · DOI
  46. Ostrander, E. L. et al. Divergent Effects of Dnmt3a and Tet2 mutations on hematopoietic progenitor cell fitness. Stem Cell Rep. 14, 551–560 (2020). · DOI · Paper page
  47. Cai, Z. et al. Inhibition of inflammatory signaling in Tet2 mutant preleukemic cells mitigates stress-induced abnormalities and clonal hematopoiesis. Cell Stem Cell 23, 833–849.e5 (2018). · DOI · Paper page
  48. Papathanasiou, P., Attema, J. L., Karsunky, H., Jian, X., Smale, S. T. & Weissman, I. L. Evaluation of the long-term reconstituting subset of hematopoietic stem cells with CD150. Stem Cells 27, 2498–2508 (2009). · DOI
  49. Ezumi, Y., Takayama, H. & Okuma, M. Thrombopoietin, c-Mpl ligand, induces tyrosine phosphorylation of Tyk2, JAK2, and STAT3, and enhances agonists-induced aggregation in platelets in vitro. FEBS Lett. https://doi.org/10.1016/0014-5793(95)01072-M (1995). · DOI
  50. Miyakawa, Y. et al. Thrombopoietin induces tyrosine phosphorylation of Stat3 and Stat5 in human blood platelets. Blood 87, 439–446 (1996). · DOI
  51. Kollmann, S. et al. A STAT5B-CD9 axis determines self-renewal in hematopoietic and leukemic stem cells. Blood 138, 2347–2359 (2021). · DOI
  52. Escamilla Gómez, V. et al. Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study. BMT https://doi.org/10.1038/s41409-019-0731-x (2020). · DOI
  53. O’Shea, J. J., Kontzias, A., Yamaoka, K., Tanaka, Y. & Laurence, A. Janus kinase inhibitors in autoimmune diseases. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2012-202576 (2013). · DOI
  54. Vainchenker, W. et al. JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders. F1000Res 7, 82 (2018). · DOI
  55. Gozgit, J. M. et al. Effects of the JAK2 inhibitor, AZ960, on Pim/BAD/BCL-xL survival signaling in the human JAK2 V617F cell line SET-2. J. Biol. Chem. https://doi.org/10.1074/jbc.M803813200 (2008). · DOI
  56. Wernig, G. et al. Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell 13, 311–320 (2008). · DOI
  57. Mascarenhas, J. & Hoffman, R. Ruxolitinib: The first FDA approved therapy for the treatment of myelofibrosis. Clin. Cancer Res. 18, 3008–3014 (2012). · DOI
  58. Nakauchi, Y. et al. The cell type-specific 5hmc landscape and dynamics of healthy human hematopoiesis and TET2-mutant preleukemia. Blood Cancer Discov. 3, 346–367 (2022). · DOI · Paper page
  59. Jeong, J. J. et al. Cytokine-regulated phosphorylation and activation of TET2 by JAK2 in hematopoiesis. Cancer Discov. 9, 778–795 (2019). · DOI
  60. Abegunde, S. O., Buckstein, R., Wells, R. A. & Rauh, M. J. An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59, 60–65 (2018). · DOI · Paper page
  61. Feng, Y. et al. Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood. https://doi.org/10.1182/blood-2010-03-276501 (2010). · DOI
  62. Nguyen, A. T., He, J., Taranova, O. & Zhang, Y. Essential role of DOT1L in maintaining normal adult hematopoiesis. Cell Res 21, 1370–1373 (2011). · DOI
  63. Kang, J. Y. et al. KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1–mediated chromatin silencing. FASEB J. 32, 5737–5750 (2018). · DOI
  64. Warren, J. T. & Link, D. C. Clonal hematopoiesis and risk for hematologic malignancy. Blood 136, 1599–1605 (2020).
  65. Jaiswal, S. Clonal hematopoiesis and nonhematologic disorders. Blood 136, 1606–1614 (2020).
  66. Flores-Guzmán, P., Fernández-Sánchez, V. & Mayani, H. Concise review: ex vivo expansion of cord blood-derived hematopoietic stem and progenitor cells: basic principles, experimental approaches, and impact in regenerative medicine. Stem Cells Transl. Med. 2, 830–838 (2013). · DOI
  67. Dahlberg, A., Delaney, C. & Bernstein, I. D. Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 117, 6083–6090 (2011). · DOI
  68. Wang, Y. et al. Tracking hematopoietic precursor division ex vivo in real time. Stem Cell Res. Ther. https://doi.org/10.1186/S13287-017-0767-Z (2018). · DOI
  69. Bolton, K. L. et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat. Genet. 52, 1219–1226 (2020). · DOI · Paper page
  70. Dorsheimer, L. et al. Association of mutations contributing to clonal hematopoiesis with prognosis in chronic ischemic heart failure. JAMA Cardiol. 4, 25–33 (2019). · DOI · Paper page
  71. Jaiswal, S. & Libby, P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat. Rev. Cardiol. 17, 137–144 (2020). · DOI · Paper page

Cited by

Metadata

Authors
Yang, Y., Cathelin, S., Liu, A. C. H., Subedi, A., Maher, A., Hosseini, M., Manikoth Ayyathan, D., Vanner, R., & Chan, S. M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-03-10
Volume
16
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-025-57614-y
PMC
PMC11894142
Cited by
14
References
8
Language
en
Licence
Funders
  • Leukemia and Lymphoma Society of Canada
  • University of Toronto
  • Gouvernement du Canada | Canadian Institutes of Health Research

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review