Abstract
The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell–activating pathways.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Primary accessions
BioProject
Gene Expression Omnibus
References
De Silva, N.S. & Klein, U. Dynamics of B cells in germinal centres. Nat. Rev. Immunol. 15, 137–148 (2015).
Kridel, R., Sehn, L.H. & Gascoyne, R.D. Pathogenesis of follicular lymphoma. J. Clin. Invest. 122, 3424–3431 (2012).
Morin, R.D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B cell lymphoma. Nature 471, 189–195 (2011).
Hu, D. et al. The MLL3-MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell. Biol. 33, 4745–4754 (2013).
Herz, H.M. et al. Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4. Genes Dev. 26, 2604–2620 (2012).
Lee, J.E. et al. H3K4 mono- and dimethyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013).
Herz, H.M., Hu, D. & Shilatifard, A. Enhancer malfunction in cancer. Mol. Cell 53, 859–866 (2014).
Egle, A. VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276–2283 (2004).
Oricchio, E. et al. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 147, 554–564 (2011).
Stadtfeld, M. & Graf, T. Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by noninvasive lineage tracing. Development 132, 203–213 (2005).
Santos, M.A. et al. DNA damage–induced differentiation of leukemic cells as an anti-cancer barrier. Nature 514, 107–111 (2014).
Hoffman, J.D. et al. Immune abnormalities are a frequent manifestation of Kabuki syndrome. Am. J. Med. Genet. A. 135, 278–281 (2005).
Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B cell lymphoma. Nature 459, 717–721 (2009).
Molavi, O. et al. Gene methylation and silencing of SOCS3 in mantle cell lymphoma. Br. J. Haematol. 161, 348–356 (2013).
Cheung, K.J. et al. Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res. 70, 9166–9174 (2010).
Guo, C. et al. KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation. Oncotarget 4, 2144–2153 (2013).
Sarma, V. et al. Activation of the B cell surface receptor CD40 induces A20, a novel zinc-finger protein that inhibits apoptosis. J. Biol. Chem. 270, 12343–12346 (1995).
Hsing, Y., Hostager, B.S. & Bishop, G.A. Characterization of CD40 signaling determinants regulating nuclear factor-kappa B activation in B lymphocytes. J. Immunol. 159, 4898–4906 (1997).
Hollmann, C.A., Owens, T., Nalbantoglu, J., Hudson, T.J. & Sladek, R. Constitutive activation of extracellular signal–regulated kinase predisposes diffuse large B cell lymphoma cell lines to CD40-mediated cell death. Cancer Res. 66, 3550–3557 (2006).
Bjornsson, H.T. et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Sci. Transl. Med. 6, 256ra135 (2014).
Højfeldt, J.W., Agger, K. & Helin, K. Histone lysine demethylases as targets for anticancer therapy. Nat. Rev. Drug Discov. 12, 917–930 (2013).
Li, H. & Durbin, R. Fast and accurate short-read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Jiang, Y., Soong, T.D., Wang, L., Melnick, A.M. & Elemento, O. Genome-wide detection of genes targeted by non-Ig somatic hypermutation in lymphoma. PLoS ONE 7, e40332 (2012).
Wacker, S.A., Houghtaling, B.R., Elemento, O. & Kapoor, T.M. Using transcriptome sequencing to identify mechanisms of drug action and resistance. Nat. Chem. Biol. 8, 235–237 (2012).
Rajadhyaksha, A.M. et al. Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. Am. J. Hum. Genet. 87, 643–654 (2010).
Scott, D.W. et al. Determining cell-of-origin subtypes of diffuse large B cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood 123, 1214–1217 (2014).
Hans, C.P. et al. Confirmation of the molecular classification of diffuse large B cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103, 275–282 (2004).
Wendel, H.G. et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428, 332–337 (2004).
Dickins, R.A. et al. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nat. Genet. 37, 1289–1295 (2005).
Béguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).
Mavrakis, K.J. et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev. 22, 2178–2188 (2008).
Hanna, J. et al. Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency. Cell 133, 250–264 (2008).
Ehlich, A., Martin, V., Muller, W. & Rajewsky, K. Analysis of the B cell progenitor compartment at the level of single cells. Curr. Biol. 4, 573–583 (1994).
Gostissa, M. et al. Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center–derived B cell lymphomas. Proc. Natl. Acad. Sci. USA 110, 2934–2939 (2013).
Brochet, X., Lefranc, M.P. & Giudicelli, V. IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res. 36, W503–W508 (2008).
Robbiani, D.F. et al. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135, 1028–1038 (2008).
Ci, W. et al. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood 113, 5536–5548 (2009).
Lee, T.I., Johnstone, S.E. & Young, R.A. Chromatin immunoprecipitation and microarray-based analysis of protein location. Nat. Protoc. 1, 729–748 (2006).
Goodarzi, H., Elemento, O. & Tavazoie, S. Revealing global regulatory perturbations across human cancers. Mol. Cell 36, 900–911 (2009).
Cover, T.M. & Thomas, J.A. Elements of Information Theory (Wiley-Interscience, Hoboken, N.J., 2006).
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).
Shaffer, A.L. et al. A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol. Rev. 210, 67–85 (2006).
Mootha, V.K. et al. PGC-1α–responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
Mavrakis, K.J. & Wendel, H.G. Translational control and cancer therapy. Cell Cycle 7, 2791–2794 (2008).
Lin, S. & Garcia, B.A. Examining histone posttranslational modification patterns by high-resolution mass spectrometry. Methods Enzymol. 512, 3–28 (2012).
Yuan, Z.F. et al. EpiProfile quantifies histone peptides with modifications by extracting retention time and intensity in high-resolution mass spectra. Mol. Cell. Proteomics 14, 1696–1707 (2015).
Festing, M.F.W. & Laboratory Animals Ltd. The Design of Animal Experiments: Reducing the Use of Animals in Research Through Better Experimental Design (Royal Society of Medicine, London, 2002).
Acknowledgements
We thank E. Oricchio (MSKCC), V. Sanghvi (MSKCC), M. Boice (MSKCC), W. Beguelin and M. del Pilar Dominguez Rodriguez (Weill Cornell Medical College) for advice and reagents. Thanks to E. de Stanchina and all of the members of the MSK Antitumor assessment core for technical assistance with mice, the MSK Laboratory of Comparative Pathology, the MSK Flow Cytometry and MSK Molecular Cytology cores, H. Hagenau for Southern blot analysis and B. Sleckman for IgκIII probe. A.O.-M. is supported by funding from The Leukemia & Lymphoma Society. H.G.W. is supported by the American Cancer Society grant RSG-13-048-01-LIB, the Lymphoma Research Foundation, Cycle for Survival, W.H. Goodwin and A. Goodwin and the Commonwealth Foundation for Cancer Research, the Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center, US National Institutes of Health (NIH) grants RO1CA183876-01 and 1R01CA19038-01 and Core Grant P30 CA008748. H.G.W. is a Scholar of the Leukemia and Lymphoma Society. A.M.M. is supported by NIH grant R01CA187109, the Chemotherapy Foundation and is a Scholar of the Burroughs Wellcome Foundation. I.W.B. is supported by a Sass Foundation Post-doctoral Fellowship award. B.A.G. acknowledges funding from an NIH Innovator grant (DP2OD007447) from the Office of the Director and NIH grant R01GM110174. A.S.H. is supported by NIH grant R01CA150265. The work in the K.G. laboratory was supported by the Intramural Research Program of the NIDDK, NIH. The work in the A.N. laboratory was supported by the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research, a Department of Defense grant (BCRP DOD Idea Expansion Award, grant 11557134) and the Alex Lemonade Stand Foundation Award.
Author information
Authors and Affiliations
Contributions
A.O.-M. designed and performed functional studies, analyzed data and wrote the manuscript; I.W.B. designed experiments, performed epigenetic studies and analyzed data; A.C. performed studies on Kmt2d−/− mice with the help of H.-T.C.; H.P. and O.E. performed RNA-seq and ChIP-Seq analysis; Y.J. and O.E. performed and analyzed exome sequencing and targeted resequencing in FL samples; C.Z. and M.J. provided technical assistance; D.H. and A.S. performed and analyzed KMT2D ChIP-seq in DLBCL cell lines; X.A. performed KMT2D expression analysis in B cell populations; I.N. performed CD40 and IgM stimulation experiments on lymphoma cell lines; K.G. and J.-E.L. generated the Kmt2dfl/fl mice; D.E., D.W.S., C.H., A.M. and R.D.G. performed KMT2D sequencing and cell-of-origin determination in DLBCL samples; S.L., X.-J.C. and B.A.G. performed quantitative mass spectrometry analysis of lymphoma cell lines; R.S. performed pathological evaluation of mouse models; W.T. provided critical clinical samples; A.N. supervised the experiments on Kmt2d−/− mice; and A.M.M. and H.-G.W. designed and directed the study.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–7 & Supplementary Tables 1–6 (PDF 12678 kb)
Rights and permissions
About this article
Cite this article
Ortega-Molina, A., Boss, I., Canela, A. et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med 21, 1199–1208 (2015). https://doi.org/10.1038/nm.3943
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.3943
This article is cited by
-
lncCPSET1 acts as a scaffold for MLL2/COMPASS to regulate Bmp4 and promote the formation of chicken primordial germ cells
Molecular Genetics and Genomics (2024)
-
Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1
Genes & Genomics (2024)
-
Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma
Nature Communications (2023)
-
A case of cold agglutinin syndrome associated with chronic lymphocytic leukaemia harbouring mutations in CARD11 and KMT2D
International Journal of Hematology (2023)
-
UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease
Leukemia (2023)