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Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness

Ostrander, Elizabeth L., Kramer, Ashley C., Mallaney, Cates, Celik, Hamza, Koh, Won Kyun, Fairchild, Jake, Haussler, Emily, Zhang, Christine R.C., Challen, Grant A.·2020·Stem Cell Reports
DOI 10.1016/j.stemcr.2020.02.011PMC PMC7160307
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Figure 1 Loss of Dnmt3a and Tet2 Enhance Self-Renewal in HSCs to Different Degrees (A) HSC serial transplantation schematic. In descending column order—contribution of 200 ControlMx1, Dnmt3a-KOMx1 (3aKO), and Tet2-KOMx1 (T2KO) HSCs to peripheral blood, lineage chimerism, HSC frequency, and HSC number in (B) primary (CNT n = 28; 3aKO n = 24; T2KO n = 22), (C) secondary (CNT n = 27; 3aKO n = 19; T2KO n = 21), and (D) tertiary (CNT n = 33; 3aKO n = 23; T2KO n = 19) transplants. (E) Self-renewal and (F) differentiation quotients of indicated HSC genotypes after each transplant. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001. Mean ± SEM is shown.
Figure 1 Loss of Dnmt3a and Tet2 Enhance Self-Renewal in HSCs to Different Degrees (A) HSC serial transplantation schematic. In descending column order—contribution of 200 ControlMx1, Dnmt3a-KOMx1 (3aKO), and Tet2-KOMx1 (T2KO) HSCs to peripheral blood, lineage chimerism, HSC frequency, and HSC number in (B) primary (CNT n = 28; 3aKO n = 24; T2KO n = 22), (C) secondary (CNT n = 27; 3aKO n = 19; T2KO n = 21), and (D) tertiary (CNT n = 33; 3aKO n = 23; T2KO n = 19) transplants. (E) Self-renewal and (F) differentiation quotients of indicated HSC genotypes after each transplant. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001. Mean ± SEM is shown.CC BY-NC-ND · PubMed Central
Figure 2 Tet2 and Dnmt3a Loss of Function Divergently Influence Rate of Transformation from Same Co-operating Mutation (A) Kaplan-Meier plot comparing time to morbidity between ControlVav (n = 30), Flt3ITD (n = 20), Dnmt3a-KOVav (n = 15), Tet2-KOVav (n = 11), Dnmt3a-KOVavFlt3ITD (n = 16), and Tet2-KOVavFlt3ITD (n = 12) mice. (B) White blood cell count of day 600 ControlVav and moribund mice of indicated genotypes. (C) Pathological diagnosis of moribund mice. (D) Representative flow cytometry plots of moribund mice demonstrating expansion of MPP3 (red box) and depletion of HSCs (purple box) in Flt3ITD genotypes. (E) Frequency and number of HSCs and MPP3 in moribund mice. (F–J) (F) Frequency and number of HSCs and MPP3 in 8-week-old ControlVav (n = 18), Flt3ITD (n = 14), Dnmt3a-KOVav (n = 18), Dnmt3a-KOVavFlt3ITD (n = 10), Tet2-KOVav (n = 15), and Tet2-KOVavFlt3ITD (n = 9) mice. Pathological analysis of young adult mice showing (G) WBC counts, (H) peripheral blood myeloid cells, (I) spleen weights, and (J) spleen myeloid cells. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001. Mean ± SEM is shown.
Figure 2 Tet2 and Dnmt3a Loss of Function Divergently Influence Rate of Transformation from Same Co-operating Mutation (A) Kaplan-Meier plot comparing time to morbidity between ControlVav (n = 30), Flt3ITD (n = 20), Dnmt3a-KOVav (n = 15), Tet2-KOVav (n = 11), Dnmt3a-KOVavFlt3ITD (n = 16), and Tet2-KOVavFlt3ITD (n = 12) mice. (B) White blood cell count of day 600 ControlVav and moribund mice of indicated genotypes. (C) Pathological diagnosis of moribund mice. (D) Representative flow cytometry plots of moribund mice demonstrating expansion of MPP3 (red box) and depletion of HSCs (purple box) in Flt3ITD genotypes. (E) Frequency and number of HSCs and MPP3 in moribund mice. (F–J) (F) Frequency and number of HSCs and MPP3 in 8-week-old ControlVav (n = 18), Flt3ITD (n = 14), Dnmt3a-KOVav (n = 18), Dnmt3a-KOVavFlt3ITD (n = 10), Tet2-KOVav (n = 15), and Tet2-KOVavFlt3ITD (n = 9) mice. Pathological analysis of young adult mice showing (G) WBC counts, (H) peripheral blood myeloid cells, (I) spleen weights, and (J) spleen myeloid cells. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001. Mean ± SEM is shown.CC BY-NC-ND · PubMed Central
Figure 3 Tet2 Mutation Does Not Impart Ectopic Self-Renewal to Hematopoietic Progenitors, but Skews Myeloid Differentiation of Committed Progenitor Cells (A) Donor-derived peripheral blood cells and 16-week lineage chimerism in recipients of 200 MPP1 from ControlVav (n = 8), Dnmt3a-KOVav (n = 7), and Tet2-KOVav (n = 5) mice. (B) Frequency of MPP1-transplanted mice with >1% donor-derived engraftment in myeloid, B cell, and T cell lineages. (C) Representative plots showing donor-derived MPP1 and HSCs in recipients of Dnmt3a-KOVav MPP1. (D) Frequency and chimerism of donor-derived HSCs and MPP1 in recipients of 200 MPP1. (E) Representative immunophenotyping of in vitro differentiated progenitor cells. (F) Immunophenotypic populations produced via in vitro differentiation of progenitor cells from ControlVav and Tet2-KOVav mice (n = 4 per population of each genotype). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001. Mean ± SEM is shown.
Figure 3 Tet2 Mutation Does Not Impart Ectopic Self-Renewal to Hematopoietic Progenitors, but Skews Myeloid Differentiation of Committed Progenitor Cells (A) Donor-derived peripheral blood cells and 16-week lineage chimerism in recipients of 200 MPP1 from ControlVav (n = 8), Dnmt3a-KOVav (n = 7), and Tet2-KOVav (n = 5) mice. (B) Frequency of MPP1-transplanted mice with >1% donor-derived engraftment in myeloid, B cell, and T cell lineages. (C) Representative plots showing donor-derived MPP1 and HSCs in recipients of Dnmt3a-KOVav MPP1. (D) Frequency and chimerism of donor-derived HSCs and MPP1 in recipients of 200 MPP1. (E) Representative immunophenotyping of in vitro differentiated progenitor cells. (F) Immunophenotypic populations produced via in vitro differentiation of progenitor cells from ControlVav and Tet2-KOVav mice (n = 4 per population of each genotype). ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.001. Mean ± SEM is shown.CC BY-NC-ND · PubMed Central
Figure 4 Dnmt3a and Tet2 Loss of Function Alter Hematopoietic Progenitor Function through Distinct Molecular Mechanisms (A) Principal-component analysis plot of gene expression in ControlVav HSCs (n = 3) and MPP3 (n = 4), Dnmt3a-KOVav HSCs (n = 3), and Tet2-KOVav HSCs (n = 4) and MPP3 (n = 4). (B) Venn diagrams displaying DEG overlap in Dnmt3a-KOVav and Tet2-KOVav HSCs compared with ControlVav HSCs. (C) Heatmaps displaying DEGs (p < 0.05, fold-change >1 or <−1) between ControlVav and Tet2-KOVav HSCs and MPP3. (D) Gene set enrichment analysis showing differentially regulated pathways between ControlVav and Tet2-KOVav MPP3. (E) Gene score enrichment plot of “Hallmark TNFα Signaling via NFkB” gene set in Tet2-KOVav MPP3. (F) ATAC-seq heatmaps from ControlVav, Dnmt3a-KOVav, and Tet2-KOVav mice. Signals displayed are peaks 1 kb up- and downstream of transcription start sites of protein coding genes. (G) Multi-dimensional scaling plot with distances approximating the largest log2 fold-changes in the top 500 peaks between ATAC-seq samples.
Figure 4 Dnmt3a and Tet2 Loss of Function Alter Hematopoietic Progenitor Function through Distinct Molecular Mechanisms (A) Principal-component analysis plot of gene expression in ControlVav HSCs (n = 3) and MPP3 (n = 4), Dnmt3a-KOVav HSCs (n = 3), and Tet2-KOVav HSCs (n = 4) and MPP3 (n = 4). (B) Venn diagrams displaying DEG overlap in Dnmt3a-KOVav and Tet2-KOVav HSCs compared with ControlVav HSCs. (C) Heatmaps displaying DEGs (p < 0.05, fold-change >1 or <−1) between ControlVav and Tet2-KOVav HSCs and MPP3. (D) Gene set enrichment analysis showing differentially regulated pathways between ControlVav and Tet2-KOVav MPP3. (E) Gene score enrichment plot of “Hallmark TNFα Signaling via NFkB” gene set in Tet2-KOVav MPP3. (F) ATAC-seq heatmaps from ControlVav, Dnmt3a-KOVav, and Tet2-KOVav mice. Signals displayed are peaks 1 kb up- and downstream of transcription start sites of protein coding genes. (G) Multi-dimensional scaling plot with distances approximating the largest log2 fold-changes in the top 500 peaks between ATAC-seq samples.CC BY-NC-ND · PubMed Central

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Citations

Cites

Research works printed but not linked: 18

  1. Buscarlet, 2018, Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A, Blood, 132, 277, 10.1182/blood-2018-01-829937 · DOI · Paper page
  2. Celik, 2018, JARID2 functions as a tumor suppressor in myeloid neoplasms by repressing self-renewal in hematopoietic progenitor cells, Cancer Cell, 34, 741, 10.1016/j.ccell.2018.10.008 · DOI
  3. Challen, 2012, Dnmt3a is essential for hematopoietic stem cell differentiation, Nat. Genet., 44, 23, 10.1038/ng.1009 · DOI · Paper page
  4. Challen, 2014, Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells, Cell Stem Cell, 15, 350, 10.1016/j.stem.2014.06.018 · DOI · Paper page
  5. Corces, 2017, An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues, Nat. Methods, 14, 959, 10.1038/nmeth.4396 · DOI · Paper page
  6. Georgiades, 2002, VavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages, Genesis, 34, 251, 10.1002/gene.10161 · DOI
  7. Kaneda, 2004, Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting, Nature, 429, 900, 10.1038/nature02633 · DOI
  8. Koh, 2011, Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells, Cell Stem Cell, 8, 200, 10.1016/j.stem.2011.01.008 · DOI · Paper page
  9. Kramer, 2017, Dnmt3a regulates T-cell development and suppresses T-ALL transformation, Leukemia, 31, 2479, 10.1038/leu.2017.89 · DOI · Paper page
  10. Kuhn, 1995, Inducible gene targeting in mice, Science, 269, 1427, 10.1126/science.7660125 · DOI · Paper page
  11. Lee, 2007, FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia, Cancer Cell, 12, 367, 10.1016/j.ccr.2007.08.031 · DOI
  12. Li, 2011, Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies, Blood, 118, 4509, 10.1182/blood-2010-12-325241 · DOI · Paper page
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  15. Sardina, 2018, Transcription factors drive tet2-mediated enhancer demethylation to reprogram cell fate, Cell Stem Cell, 23, 905, 10.1016/j.stem.2018.11.001 · DOI
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  17. Wang, 2018, TET2 coactivates gene expression through demethylation of enhancers, Sci. Adv., 4, eaau6986, 10.1126/sciadv.aau6986 · DOI
  18. Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat. Med., 20, 1472, 10.1038/nm.3733 · DOI · Paper page

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Metadata

Authors
Ostrander, E. L., Kramer, A. C., Mallaney, C., Celik, H., Koh, W. K., Fairchild, J., Haussler, E., Zhang, C. R. C., & Challen, G. A.
Venue
Stem Cell Reports
Publisher
Elsevier BV
Published
2020-04
Volume
14
Issue
4
Pages
551-560
ISSN
2213-6711
DOI
10.1016/j.stemcr.2020.02.011
PMC
PMC7160307
Cited by
94
References
12
Language
en
Licence
Funders
  • National Institutes of Health
  • Gabrielle’s Angel Foundation for Cancer Research
  • American Society of Hematology
  • Leukemia and Lymphoma Society
  • Longer Life Foundation
  • Edward P. Evans Foundation
  • Edward Mallinckrodt, Jr. Foundation
  • National Institute of Diabetes and Digestive and Kidney Diseases

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