Abstract
The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation poised state in HSCs due to the increased expression of the AP-1 transcription factor complex (Fos and Jun) and immediate early response (IER) genes. These gene expression changes occurred independently of chromatin modifications. Targeting AP-1 restored function of Kdm6b-deficient HSCs, suggesting that Kdm6b regulates this complex during HSC stress response. We also show Kdm6b supports developmental context-dependent leukemogenesis for T-cell acute lymphoblastic leukemia (T-ALL) and M5 acute myeloid leukemia (AML). Kdm6b is required for effective fetal-derived T-ALL and adult-derived AML, but not vice versa. These studies identify a crucial role for Kdm6b in regulating HSC self-renewal in different contexts, and highlight the potential of KDM6B as a therapeutic target in different hematopoietic malignancies.
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References
Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA. 2007;104:18439–44.
Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21:381–95.
Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94.
Sen GL, Webster DE, Barragan DI, Chang HY, Khavari PA. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 2008;22:1865–70.
Burgold T, Voituron N, Caganova M, Tripathi PP, Menuet C, Tusi BK, et al. The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival. Cell Rep. 2012;2:1244–58.
Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, et al. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007;449:731–4.
De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, et al. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. Embo J. 2009;28:3341–52.
De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell. 2007;130:1083–94.
Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488:404–8.
Wijayatunge R, Chen LF, Cha YM, Zannas AS, Frank CL, West AE. The histone lysine demethylase Kdm6b is required for activity-dependent preconditioning of hippocampal neuronal survival. Mol Cell Neurosci. 2014;61:187–200.
Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009;23:1171–6.
Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenfuhr M, et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009;23:1177–82.
Ohguchi H, Harada T, Sagawa M, Kikuchi S, Tai YT, Richardson PG, et al. KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia. 2017;31:2661–9.
Greenblatt SM, Nimer SD. Chromatin modifiers and the promise of epigenetic therapy in acute leukemia. Leukemia. 2014;28:1396–406.
Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 2013;121:3563–72.
Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
Mar BG, Bullinger L, Basu E, Schlis K, Silverman LB, Dohner K, et al. Sequencing histone-modifying enzymes identifies UTX mutations in acute lymphoblastic leukemia. Leukemia. 2012;26:1881–3.
Kiel MJ, Sahasrabuddhe AA, Rolland DC, Velusamy T, Chung F, Schaller M, et al. Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sezary syndrome. Nat Commun. 2015;6:8470.
Wei Y, Chen R, Dimicoli S, Bueso-Ramos C, Neuberg D, Pierce S, et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia. 2013;27:2177–86.
Anderton JA, Bose S, Vockerodt M, Vrzalikova K, Wei W, Kuo M, et al. The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over-expressed in Hodgkin’s Lymphoma. Oncogene. 2011;30:2037–43.
Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature. 2014;514:513–7.
Yu SH, Zhu KY, Chen J, Liu XZ, Xu PF, Zhang W, et al. JMJD3 facilitates C/EBPbeta-centered transcriptional program to exert oncorepressor activity in AML. Nat Commun. 2018;9:3369.
Wei Y, Zheng H, Bao N, Jiang S, Bueso-Ramos CE, Khoury J, et al. KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice. Blood Adv. 2018;2:2491–504.
Iwamori N, Iwamori T, Matzuk MM. H3K27 demethylase, JMJD3, regulates fragmentation of spermatogonial cysts. PLoS ONE. 2013;8:e72689.
Wang C, Lee JE, Cho YW, Xiao Y, Jin Q, Liu C, et al. UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci USA. 2012;109:15324–9.
Georgiades P, Ogilvy S, Duval H, Licence DR, Charnock-Jones DS, Smith SK, et al. VavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages. Genesis. 2002;34:251–6.
Kuhn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science. 1995;269:1427–9.
Hayashi S, McMahon AP. Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol. 2002;244:305–18.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.
Liao Y, Smyth GK, Shi W. The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic Acids Res. 2013;41:e108.
Patro R, Mount SM, Kingsford C. Sailfish enables alignment-free isoform quantification from RNA-seq reads using lightweight algorithms. Nat Biotechnol. 2014;32:462–4.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.
Schmidl C, Rendeiro AF, Sheffield NC, Bock C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat Methods. 2015;12:963–5.
Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9:357–9.
Starmer J, Magnuson T. Detecting broad domains and narrow peaks in ChIP-seq data with hiddenDomains. BMC Bioinformatics. 2016;17:144.
Carroll TS, Liang Z, Salama R, Stark R, de Santiago I. Impact of artifact removal on ChIP quality metrics in ChIP-seq and ChIP-exo data. Front Genet. 2014;5:75.
Ramirez F, Ryan DP, Gruning B, Bhardwaj V, Kilpert F, Richter AS, et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016;44:W160–5.
Neph S, Kuehn MS, Reynolds AP, Haugen E, Thurman RE, Johnson AK, et al. BEDOPS: high-performance genomic feature operations. Bioinformatics. 2012;28:1919–20.
Corces MR, Trevino AE, Hamilton EG, Greenside PG, Sinnott-Armstrong NA, Vesuna S, et al. An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues. Nat Methods. 2017;14:959–62.
Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, et al. Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nat Commun. 2014;5:5780.
Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009;347:70–8.
Kirschner K, Chandra T, Kiselev V, Flores-Santa Cruz D, Macaulay IC, Park HJ, et al. Proliferation drives aging-related functional decline in a subpopulation of the hematopoietic stem cell compartment. Cell Rep. 2017;19:1503–11.
Tullai JW, Schaffer ME, Mullenbrock S, Sholder G, Kasif S, Cooper GM. Immediate-early and delayed primary response genes are distinct in function and genomic architecture. J Biol Chem. 2007;282:23981–95.
Venezia TA, Merchant AA, Ramos CA, Whitehouse NL, Young AS, Shaw CA, et al. Molecular signatures of proliferation and quiescence in hematopoietic stem cells. PLoS Biol. 2004;2:e301.
Fortier ME, Kent S, Ashdown H, Poole S, Boksa P, Luheshi GN. The viral mimic, polyinosinic:polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2004;287:R759–66.
Yamazaki S, Tanaka Y, Araki H, Kohda A, Sanematsu F, Arasaki T, et al. The AP-1 transcription factor JunB is required for Th17 cell differentiation. Sci Rep. 2017;7:17402.
Leppa S, Eriksson M, Saffrich R, Ansorge W, Bohmann D. Complex functions of AP-1 transcription factors in differentiation and survival of PC12 cells. Mol Cell Biol. 2001;21:4369–78.
Han B, Rorke EA, Adhikary G, Chew YC, Xu W, Eckert RL. Suppression of AP1 transcription factor function in keratinocyte suppresses differentiation. PLoS ONE. 2012;7:e36941.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.
Xiang Y, Zhu Z, Han G, Lin H, Xu L, Chen CD. JMJD3 is a histone H3K27 demethylase. Cell Res. 2007;17:850–7.
Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med. 1996;183:2283–91.
Lord KA, Abdollahi A, Hoffman-Liebermann B, Liebermann DA. Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation. Mol Cell Biol. 1993;13:841–51.
Okada S, Fukuda T, Inada K, Tokuhisa T. Prolonged expression of c-fos suppresses cell cycle entry of dormant hematopoietic stem cells. Blood. 1999;93:816–25.
Li Y, Zhang M, Sheng M, Zhang P, Chen Z, Xing W, et al. Therapeutic potential of GSK-J4, a histone demethylase KDM6B/JMJD3 inhibitor, for acute myeloid leukemia. J Cancer Res Clin Oncol. 2018;144:1065–77.
Van der Meulen J, Sanghvi V, Mavrakis K, Durinck K, Fang F, Matthijssens F, et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood. 2015;125:13–21.
Acknowledgments
We thank Dr. Martin Matzuk (Baylor College of Medicine) for providing Kdm6bfl/fl mice, Dr. Lukas Wartman (Washington University) for providing Utx1fl/fl mice, and Dr. Jeff Magee (Washington University) for providing MLL-AF9 retroviral plasmid. We thank the Alvin J. Siteman Cancer Center at Washington University for use of the Siteman Flow Cytometry Core, supported in part by NCI Grant CA91842. We thank the Genome Technology Access Center at Washington University for genomic analysis, partially supported by NCI Grant CA91842 and by ICTS/CTSA Grant UL1TR000448 NIH. This work was supported by the National Institutes of Health (R01DK102428), the Edward Mallinckrodt Jr. Foundation, the American Society of Hematology, the V Foundation, Gabrielle’s Angel Foundation, and the Sidney Kimmel Foundation (all to GAC). Bioinformatics analysis was supported by the Washington University Center for Regenerative Medicine. CM was supported by NIH T32HL007088, and NIH DK111058-01. ELO was supported by NIH 5T32CA113275-10 and NIH F31DK114951. HC was supported by a post-doctoral scholar award from the American Society of Hematology and an Edward P. Evans Foundation Young Investigator Award. GAC is a Leukemia and Lymphoma Society scholar.
Author contirbutions
Project conceptualization and experimental design: GAC. Performed experiments: CM, ELO, HC, ACK, AM, AK, WKK, EH, GAC. Provided critical reagents: NI. Data analysis: CM, ELO, PG, BZ, GAC. Writing—original draft preparation: CM. Writing—review and editing: GAC. Project administration and funding acquisition: GAC.
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Mallaney, C., Ostrander, E.L., Celik, H. et al. Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia 33, 2506–2521 (2019). https://doi.org/10.1038/s41375-019-0462-4
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DOI: https://doi.org/10.1038/s41375-019-0462-4
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