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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

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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

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Cited by

See all 14

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

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