Abstract
The methylcytosine dioxygenase TET1 (‘ten-eleven translocation 1’) is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.
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Change history
17 June 2015
In the version of this article initially published, labels reading "5hmC gain" were incorrectly included below the plots in Figure 6e, and the plot at right was mislabeled above (as "loss"). The plot at left should have a single label above reading "5hmC loss" and the plot at right should have a single label above reading "5hmC gain." The error has been corrected in the HTML and PDF versions of the article.
References
Dawson, M.A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).
Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).
Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).
Guo, J.U., Su, Y., Zhong, C., Ming, G.L. & Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423–434 (2011).
Yang, H. et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 32, 663–669 (2013).
Kudo, Y. et al. Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci. 103, 670–676 (2012).
Xu, Y. et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451–464 (2011).
Stroud, H., Feng, S., Morey Kinney, S., Pradhan, S. & Jacobsen, S.E. 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol. 12, R54 (2011).
Valinluck, V. & Sowers, L.C. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res. 67, 946–950 (2007).
He, Y.F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).
Lorsbach, R.B. et al. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17, 637–641 (2003).
Ittel, A. et al. First description of the t(10;11)(q22;q23)/MLL-TET1 translocation in a T-cell lymphoblastic lymphoma, with subsequent lineage switch to acute myelomonocytic myeloid leukemia. Haematologica 98, e166–e168 (2013).
Burmeister, T. et al. The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group. Blood 113, 4011–4015 (2009).
The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 1 (2013).
De Keersmaecker, K. et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat. Genet. 45, 186–190 (2013).
Abdel-Wahab, O. et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114, 144–147 (2009).
Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med. 360, 2289–2301 (2009).
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).
Ko, M. et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010).
Ficz, G. et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473, 398–402 (2011).
Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–348 (2011).
Chen, J. et al. Vitamin C modulates TET1 function during somatic cell reprogramming. Nat. Genet. 45, 1504–1509 (2013).
Gao, Y. et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 12, 453–469 (2013).
Morin, R.D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).
Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat. Genet. 43, 830–837 (2011).
Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat. Genet. 46, 176–181 (2014).
Li, H. et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood 123, 1487–1498 (2014).
Dawlaty, M.M. et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9, 166–175 (2011).
Morin, R.D. et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 122, 1256–1265 (2013).
Liu, M. et al. Two levels of protection for the B cell genome during somatic hypermutation. Nature 451, 841–845 (2008).
Shaffer, A.L. III, Young, R.M. & Staudt, L.M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol. 30, 565–610 (2012).
Pasqualucci, L. et al. AID is required for germinal center-derived lymphomagenesis. Nat. Genet. 40, 108–112 (2008).
Ivanova, N.B. et al. A stem cell molecular signature. Science 298, 601–604 (2002).
Bhattacharyya, S. et al. Genome-wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer. Nucleic Acids Res. 41, e157 (2013).
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).
Lara-Astiaso, D. et al. Immunogenetics. Chromatin state dynamics during blood formation. Science 345, 943–949 (2014).
Campbell, C., Risueno, R.M., Salati, S., Guezguez, B. & Bhatia, M. Signal control of hematopoietic stem cell fate: Wnt, Notch, and Hedgehog as the usual suspects. Curr. Opin. Hematol. 15, 319–325 (2008).
Lin, H.K., Bergmann, S. & Pandolfi, P.P. Deregulated TGF-β signaling in leukemogenesis. Oncogene 24, 5693–5700 (2005).
Kikushige, Y. et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 20, 246–259 (2011).
The Non-Hodgkin's Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. Blood 89, 3909–3918 (1997).
De, S. et al. Aberration in DNA methylation in B-cell lymphomas has a complex origin and increases with disease severity. PLoS Genet. 9, e1003137 (2013).
Martin-Subero, J.I. et al. A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms. PLoS ONE 4, e6986 (2009).
Matsuda, I., Imai, Y. & Hirota, S. Distinct global DNA methylation status in B-cell lymphomas: immunohistochemical study of 5-methylcytosine and 5-hydroxymethylcytosine. J. Clin. Exp. Hematop. 54, 67–73 (2014).
Guo, J. et al. Differential DNA methylation of gene promoters in small B-cell lymphomas. Am. J. Clin. Pathol. 124, 430–439 (2005).
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).
Asmar, F. et al. Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. Haematologica 98, 1912–1920 (2013).
Hashimshony, T., Zhang, J., Keshet, I., Bustin, M. & Cedar, H. The role of DNA methylation in setting up chromatin structure during development. Nat. Genet. 34, 187–192 (2003).
Grant, S., Easley, C. & Kirkpatrick, P. Vorinostat. Nat. Rev. Drug Discov. 6, 21–22 (2007).
Weigert, O. et al. Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation. Cancer Discov. 2, 47–55 (2012).
Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).
Shaknovich, R. et al. DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. Blood 116, e81–e89 (2010).
Geng, H. et al. Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. Cancer Discov. 2, 1004–1023 (2012).
Brune, V. et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J. Exp. Med. 205, 2251–2268 (2008).
Ehrich, M. et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc. Natl. Acad. Sci. USA 102, 15785–15790 (2005).
Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).
Di Tullio, A. et al. CCAAT/enhancer binding protein alpha (C/EBP(α))-induced transdifferentiation of pre-B cells into macrophages involves no overt retrodifferentiation. Proc. Natl. Acad. Sci. USA 108, 17016–17021 (2011).
Adli, M., Zhu, J. & Bernstein, B.E. Genome-wide chromatin maps derived from limited numbers of hematopoietic progenitors. Nat. Methods 7, 615–618 (2010).
Akalin, A. et al. Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genet. 8, e1002781 (2012).
Acknowledgements
We thank members of the Aifantis laboratory for discussions; M. Xu and F. Yang for help and advice; L. Pasqualucci (Columbia University) for control antibodies and control tissue sections for immunohistochemistry of mouse B cell lymphomas and expertise; K. Ganz, R. Flannery, D. Fu and T. Adil for help with animal husbandry and tissue collection; A. Heguy and I. Dolgalev for assistance with microarray experiments, RNA-seq and exome sequencing; the NYU Flow Cytometry facility for cell sorting; the NYU Histology Core; and E. Oricchio for assistance with analysis of data from patients with FL. Supported by the Damon Runyon Cancer Research Foundation (M.M.D.), the US National Institutes of Health (5RO1HD045022 and 5R37CA084198 for work in the laboratory of R.J.; and 1R01CA169784, 1R01CA133379, 1R01CA105129, 1R01CA149655 and 5R01CA173636 for the Aifantis laboratory), the Simons Foundation (for work in the laboratory of R.J.), the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society (TRP#6340-11 and LLS#6373-13), The Chemotherapy Foundation, The V Foundation for Cancer Research, the Alex's Lemonade Stand Foundation for Childhood Cancer, the St. Baldrick's Cancer Research Foundation, the National Health and Medical Research Council (L.C.) and the Howard Hughes Medical Institute (I.A.).
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L.C., M.M.D., R.J. and I.A. designed and performed experiments; D.N.-L., S.Ba. and J.M. provided technical assistance; Y.S.Y. performed bisulfite-sequencing experiments; Y.Y., S.Bh. and A.K.V. performed, analyzed and provided bioinformatics support for HELP-GT assays; R.S. and H.G. provided bioinformatics support for patient HELP assays and RNA-seq; and R.S. performed MassArray experiments; C.Lo., B.K., T.T., B.A.-O. and S.S. participated in bioinformatics analysis; C.Li. provided histopathology advice; and L.C. and I.A. wrote the manuscript.
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Integrated supplementary information
Supplementary Figure 1 Peripheral blood analysis and organ histology of sick Tet1-deficient mice.
a) Hemavet quantification of whole blood cell numbers from Tet1+/+, Tet1+/– and Tet1–/– mice aged 18-24 months. WBC = white blood cells, RBC = red blood cells, NS = not significant, * P = <0.05. (unpaired t-test) Small horizontal lines indicate the mean; Tet1+/+ (n = 20), Tet1+/– (n = 20) and Tet1–/– (n = 32). b-c) Peripheral blood smears stained with Wright-Giemsa and d) flow cytometric analysis of peripheral blood from sick Tet1-deficient mice compared to age-matched Tet1+/+ controls. Data are representative of 3 independent experiments, n = 8-10 mice per genotype. e) Histological analysis of spleens from sick Tet1+/– and Tet1–/– mice compared to age-matched Tet1+/+ controls. Sections were stained with H&E and Ki67 as indicated. RP = Red pulp, F = Follicle. f) H&E staining of liver, lung and kidney sections from sick Tet1+/– showing diffuse lymphocytic infiltration compared to age-matched Tet1+/+ mice. g) H&E and Ki67 staining of hyperproliferative infiltrating cells in liver, lung and kidney of Tet1-deficient mice. Histology is representative of Tet1+/+, Tet1+/– and Tet1–/– mice (n = 6-8 mice per genotype). Scale bar = 100μm in all panels.
Supplementary Figure 2 Tet1-deficient B cell lymphomas display both IgM– and IgM+ phenotypes and are transplantable.
a-b) Examples of flow cytometric analysis of lymph nodes from sick Tet1+/– and Tet1–/– mice compared to age-matched Tet1+/+controls, displaying IgM–, IgM+ and CD11b+ staining patterns. c-d) H&E stained sections of liver, kidney, spleen and lymph nodes from sick Tet1+/– and Tet1–/– mice with multinucleated giant cells and histiocytic sarcoma. Scale bar = 100μm in all panels. e) White blood cell (WBC) and lymphocyte cell counts in the peripheral blood of Tet1-deficient tumor recipient mice 8 and 12 weeks post-transplant. f) Recipient mice 12 weeks post-transplant. Upper left panel; example of gross-anatomy of recipient mice with white patchy liver and enlarged spleen. Upper middle and right and lower panels; H&E staining of recipient mouse tissue histological sections, with spleen and liver infiltration, and histiocytic sarcoma in the liver. Scale bar = 100μm in all panels. g) Representative flow cytometric analysis of spleen cells from recipient mice gated on CD45.2+ donor cells co-stained for B cell (B220) and surface Ig (IgD and IgM) expression.
Supplementary Figure 3 Mutational analysis and base-substitution frequency in Tet1-deficient lymphomas.
Exome sequencing data for thirteen Tet1-deficient tumors (T1-13) were divided into 2 groups; Group 1 = low mutation frequency (<50 total exonic variations), Group 2 = high mutation frequency (50-1200 total exonic variations). Low (Group1) and high-grade (Group 2) mutated tumors were compared for a) average number of indels and nsSNVs, b) frequency of mutation type and c) frequency of transversion or transition base substitutions. A, T, C or G base substitution frequencies were calculated d) overall and e) in the context of transversion or transition mutation;(e) pairs of nucleotides indicate transversion mutations targeting T or A (TG: T-to-G, TA: T-to-A, AC: A-to-T, AT: A-to-T) and C or G (CA: C-to-A, CG: C-to-G, GT: G-to-T, GC: G-to-C) and transition mutations targeting T or A (TC: T-to-C, AG: A-to-G) and C or G (CT: C-to-T, GA: G-to-A). Average mutation frequency of base substitutions in f) low (Group1) and g) high-grade (Group 2) mutated Tet1-deficient tumors according to trinucleotide context with examples of individual high-grade mutated tumors; h) T12 and i) T11. Mean ± SEM (Group 1, n = 8; Group 2, n = 5).
Supplementary Figure 4 Overlapping mutations in IgM+ and IgM– Tet1-deficient tumors, hypermethylation of TET1 in mature B cell lymphomas and contrasting disease spectra of Tet1 and Tet2 deficiency in mice.
a) Frequency of IgM+ and IgM– lymphomas in Tet1-deficient mice. b) V(D)J-rearrangements in DNA of exome sequenced tumor samples. DNA isolated from total splenic cells (SP) was used as a control for the amplification of the constant heavy chain (Cμ), and for the rearrangements of D-Jh4, V7183-Jh4 and V558-Jh4, Vκ-Jκ and Vλ-Jλ. c) Venn Diagram of overlapping recurrently mutated genes in IgM+ and IgM– tumors. d) HELP assay for methylation in patient samples are shown; human naïve B (NB), centroblast B (CB), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), multiple myeloma (MM), activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL, precursor B (Pre-B), B-acute lymphoblastic leukemia (B-ALL) subtypes – BCR-ABL, E2A-PBX1, MLL-rearranged (MLLr) and other, normal T, T-acute lymphoblastic leukemia (T-ALL), CD34+ progenitor cells and acute myeloid leukemia (AML) * P ≤ 0.05, ** P ≤ 0.005 and ***P ≤ 0.0005 (Wilcoxon test). e) EpiGram of an amplicon targeting CpGs in the first intron of TET1 used in Sequenom-Targeted Methylation Analysis by Sequenom MassARRAY. Two normal human germinal center B (GCB) samples are displayed compared to 5 FL patient samples. Circles depict increasing CpG methylation status from 0-100% as indicated. f) Kaplan-Meier survival curve of Tet2-deficient mice with heterozygous (Tet2+/–) and homozygous (Tet2–/–) deletion compared to wild-type mice (Tet2+/+). * P = <0.0005 (Mantel-Cox test). Frequency of diseases; acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML), myeloid dysplasia (MDS), B cell lymphoma (BCL) and T-cell lymphoma (TCL) observed in g) Tet2- and h) Tet1-deficient mice.
Supplementary Figure 5 Tet1 deficiency causes a decrease in the frequency of mature B cells in the bone marrow and spleen.
Summary of flow cytometric analysis of the frequency of lineage positive (Lin+) cells in the a-b) bone marrow and c-d) spleen of Tet1+/+, Tet1+/– and Tet1–/– mice. B cell (B220+), T cell (CD3+), granulocyte (Gr1+), neutrophil (Gr1+CD11b+), monocyte (Gr1–CD11b+), progenitor (CD71+Ter119–), precursor (CD71+Ter119+) and mature nucleated erythroid cell (CD71– Ter119+) frequencies are shown. e-f) Summary of flow cytometric analysis to assess the frequency of B220+ B cell subsets in the bone marrow stained with IgM and IgD for progenitor and precursor B (Pro/PreB), immature (ImmB), transitional (TransB) and mature B cells (MatB). g) Representative flow cytometric analysis of the frequency of B cell subsets in the bone marrow of Tet1+/+ and moribund Tet1–/– mice. All bar graphs display the mean ± SEM (3 months, n = 4 mice per genotype; Moribund, n = 6-8 mice per genotype); * P = <0.01, ** P = <0.001, *** = P <0.0001 (unpaired t-test).
Supplementary Figure 6 Tet1-deficient HSCs display increased self-renewal in vivo with a deficiency in bone marrow mature B cells and expression of genes in histone cluster 1 in hematopoietic cell lineages.
a) Frequency of CD45.2+ competitive donor cells in total LSKs, LT-HSCs and MPPs from the bone marrow of primary transplanted mice 20-weeks post-reconstitution (mean ± SEM, n = 6 mice per genotype); * P = <0.001, ** P = <0.0001) (unpaired t-test). b) Representative flow cytometry of CD45.2+ cells from the bone marrow of primary transplanted mice. Upper panel; HSC subsets of CD45.2+ LSK cells stained for LT-HSC, ST-HSC, MPP1 and MPP2 with CD150 and CD48 as previously described. Lower panel; CD45.2+ B220+ cells stained for B cell subsets with IgM and IgD. c) Sorting strategy for microarray and RNA-seq analysis of total LSK, LT-HSC and MPP populations. d) Heat map of Histone cluster 1 gene expression in hematopoietic stem, progenitor and mature cells.
Supplementary Figure 7 5hmC losses and 5mC gains in Tet1-deficient LSK cells target genes encoding molecules involved in DNA repair, G protein– coupled receptor signaling and tumor-suppressor pathways.
a) Percent of 5hmC losses and gains across genomic regions. b) Overlap of 5hmC losses and gains with enhancer histone marks in ST-HSCs and MPPs. c) Coverage per base and d) sample clustering of RRBS data from Tet1+/+ and Tet1–/– LSKs. e) Representative frequency of CpG sites with 0-100 percent CpG methylation in Tet1+/+ and Tet1–/– LSKs. f) Ingenuity Pathway Analysis (IPA) software was used to generate schematic representations of genes that lose 5hmC and gain 5mC in Tet1–/– LSK cells. Signaling pathways displayed include genes pathways involved in tumor suppression (TGF-β, WNT/β-Catenin, p53 and PTEN), DNA repair (BER) and B cell function (RhoA, G-protein coupled). Log adjusted P-value for significance is shown along the x axis. Red lines indicate threshold of significance (P = 0.05).
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7 and Supplementary Tables 1–11 (PDF 1660 kb)
Supplementary Data Set 1
Somatic non-synonymous SNVs identified by whole exome sequencing in hematopoietic tumors from Tet1-deficient mice. (XLS 512 kb)
Supplementary Data Set 2
Somatic indels identified by whole exome sequencing in hematopoietic tumors from Tet1-deficient mice. (XLS 82 kb)
Supplementary Data Set 3
Recurrent somatic mutations identified by whole exome sequencing in hematopoietic tumors from Tet1- deficient mice. (XLS 140 kb)
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Cimmino, L., Dawlaty, M., Ndiaye-Lobry, D. et al. TET1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol 16, 653–662 (2015). https://doi.org/10.1038/ni.3148
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DOI: https://doi.org/10.1038/ni.3148
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