Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10–positive leukemias
Open accessAbstract
Chromosomal translocations generating fusion proteins are frequently found in human leukemias. The fusion proteins play an important role in leukemogenesis by subverting the function of one or both partner proteins. The leukemogenic CALM-AF10 fusion protein is capable of interacting with the histone H3 lysine 79 (H3K79)–specific methyltransferase hDOT1L through the fused AF10 moiety. This interaction leads to local H3K79 hypermethylation on Hoxa5 loci, which up-regulates the expression of Hoxa5 and contributes to leukemogenesis. However, the long latency of leukemogenesis of CALM-AF10 transgenic mice suggests that the direct effects of fusion oncogene are not sufficient for the induction of leukemia. In this study, we show that the CALM-AF10 fusion protein can also greatly reduce global H3K79 methylation in both human and murine leukemic cells by disrupting the AF10-mediated association of hDOT1L with chromatin. Cells with reduced H3K79 methylation are more sensitive to γ-irradiation and display increased chromosomal instability. Consistently, leukemia patients harboring CALM-AF10 fusion have more secondary chromosomal aberrations. These findings suggest that chromosomal instability associated with global epigenetic alteration contributes to malignant transformation in certain leukemias, and that leukemias with this type of epigenetic alteration might benefit from treatment regimens containing DNA-damaging agents. This study is registered with www.clinicaltrials.gov as NCT00266136.
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The feasibility of specifically directing either components of the DNA or histone methylation machinery for locus specific gene regulation in human cells ex vivo has already been established.
“The feasibility of specifically directing either components of the DNA or histone methylation machinery for locus specific gene regulation in human cells ex vivo has already been established 208 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [208]
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Cites
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219 · see citing works
Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
Gossen, M., & Bujard, H. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.12.5547 · Cited by 4,943 · see citing works
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515 · see citing works
The Consensus Coding Sequences of Human Breast and Colorectal Cancers
Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D. L., Leary, R. J., Ptak, J., Silliman, N., et al. (2006) · Science · doi:10.1126/science.1133427 · Cited by 3,161 · see citing works
Chromosomal translocations in human cancer
Rabbitts, T. H. (1994) · Nature · doi:10.1038/372143a0 · Cited by 1,490 · see citing works
DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome
Ley, T. J., Mardis, E. R., Ding, L., Fulton, B., McLellan, M. D., Chen, K., Dooling, D. J., Dunford-Shore, B. H., McGrath, S. D., Hickenbotham, M. T., et al. (2008) · Nature · doi:10.1038/nature07485 · Cited by 1,415 · see citing works
Botuyan, M. V., Lee, J., Ward, I. M., Kim, J., Thompson, J. R., Chen, J., & Mer, G. (2006) · Cell · doi:10.1016/j.cell.2006.10.043 · Cited by 973 · see citing works
Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks
Huyen, Y., Zgheib, O., DiTullio Jr, R. A., Gorgoulis, V. G., Zacharatos, P., Petty, T. J., Sheston, E. A., Mellert, H. S., Stavridi, E. S., & Halazonetis, T. D. (2004) · Nature · doi:10.1038/nature03114 · Cited by 884 · see citing works
Methylation of H3-Lysine 79 Is Mediated by a New Family of HMTases without a SET Domain
Feng, Q. F., Wang, H., Ng, H., Erdjument‐Bromage, H., Tempst, P., Struhl, K., & Zhang, Y. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00901-6 · Cited by 866 · see citing works
Self-citationDot1p Modulates Silencing in Yeast by Methylation of the Nucleosome Core
van Leeuwen, F., Gafken, P. R., & Gottschling, D. E. (2002) · Cell · doi:10.1016/s0092-8674(02)00759-6 · Cited by 853 · see citing works
hDOT1L Links Histone Methylation to Leukemogenesis
Okada, Y., Feng, Q. F., Lin, Y.-H., Jiang, Q., Li, Y., Coffield, V. M., Su, L., Xu, G., & Zhang, Y. (2005) · Cell · doi:10.1016/j.cell.2005.02.020 · Cited by 819 · see citing works
Self-citationKrogan, N. J., Dover, J., Wood, A., Schneider, J., Heidt, J. W., Boateng, M. A., Dean, K., Ryan, O. W., Golshani, A., Johnston, M., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00091-1 · Cited by 706 · see citing works
H3K79 methylation profiles define murine and human MLL-AF4 leukemias
Krivtsov, A., Feng, Z.-H., Lemieux, M., Faber, J., Vempati, S., Sinha, A., Xia, X.-B., Jesneck, J., Bracken, A., Silverman, L., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.10.001 · Cited by 573 · see citing works
van de Wetering, M., Oving, I. M., Muncan, V., Fong, M. T. P., Brantjes, H., van Leenen, D., Holstege, F. C. P., Brummelkamp, T. R., Agami, R., & Clevers, H. C. (2003) · EMBO Reports · doi:10.1038/sj.embor.embor865 · Cited by 512 · see citing works
Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins
Ayton, P. M., & Cleary, M. L. (2001) · Oncogene · doi:10.1038/sj.onc.1204639 · Cited by 499 · see citing works
Steger, D. J., Lefterova, M. I., Ying, L., Stonestrom, A. J., Schupp, M., Zhuo, D. X., Vakoc, A. L., Kim, J., Chen, J., Lazar, M. A., et al. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02076-07 · Cited by 499 · see citing works
Lavau, C., Szilvassy, S. J., Slany, R. K., & Cleary, M. L. (1997) · The EMBO Journal · doi:10.1093/emboj/16.14.4226 · Cited by 401 · see citing works
Jones, B. T., Su, H., Bhat, A., Lei, H., Bajko, J., Hevi, S., Baltus, G. A., Kadam, S., Zhai, H., Valdez, R., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000190 · Cited by 384 · see citing works
Self-citationTebar, F., Bohlander, S. K., & Sorkin, A. (1999) · Molecular Biology of the Cell · doi:10.1091/mbc.10.8.2687 · Cited by 320 · see citing works
Self-citationNg, H., Ciccone, D. N., Morshead, K. B., Oettinger, M. A., & Struhl, K. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0437846100 · Cited by 315 · see citing works
Dreyling, M. H., Martinez-Climent, J. A., Zheng, M., Mao, J., Rowley, J. D., & Bohlander, S. K. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.10.4804 · Cited by 310 · see citing works
Self-citationDisruptor of Telomeric Silencing-1 Is a Chromatin-specific Histone H3 Methyltransferase
Lacoste, N., Utley, R. T., Hunter, J. M., Poirier, G. G., & Côté, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200366200 · Cited by 298 · see citing works
The role of chromosome translocations in leukemogenesis.
Rowley, J. D. (1999) · PubMed · Cited by 289 · see citing works
Wysocki, R., Javaheri, A., Allard, S., Sha, F., Côté, J., & Kron, S. J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.19.8430-8443.2005 · Cited by 288 · see citing works
ETV6: A versatile player in leukemogenesis
Bohlander, S. K. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.01.008 · Cited by 206 · see citing works
Self-citationChromatin Targeting of de Novo DNA Methyltransferases by the PWWP Domain
Ge, Y., Pu, M., Gowher, H., Wu, H., Ding, J., Jeltsch, A., & Xu, G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312296200 · Cited by 206 · see citing works
Self-citationDobson, C. L., Warren, A. J., Pannell, R., Forster, A., Lavenir, I., Corral, J., Smith, A. J. H., & Rabbitts, T. H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.13.3564 · Cited by 206 · see citing works
Lavau, C., Du, C., Thirman, M. J., & Zeleznik‐Le, N. J. (2000) · The EMBO Journal · doi:10.1093/emboj/19.17.4655 · Cited by 202 · see citing works
Leukaemic transformation by CALM–AF10 involves upregulation of Hoxa5 by hDOT1L
Okada, Y., Jiang, Q., Lemieux, M., Jeannotte, L., Su, L., & Zhang, Y. (2006) · Nature Cell Biology · doi:10.1038/ncb1464 · Cited by 179 · see citing works
Self-citationRole for the Silencing Protein Dot1 in Meiotic Checkpoint Control
San-Segundo, P. A., & Roeder, G. S. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.10.3601 · Cited by 177 · see citing works
Chaplin, T., Ayton, P. M., Bernard, O., et al. (1995) · Blood · doi:10.1182/blood.v85.6.1435.bloodjournal8561435 · Cited by 168 · see citing works
Saha, V., Chaplin, T., Gregorini, A., Ayton, P. M., & Young, B. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.21.9737 · Cited by 146 · see citing works
Lavau, C., Luo, R. T., Du, C., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.190167297 · Cited by 140 · see citing works
Dichotomy of AML1-ETO Functions: Growth Arrest versus Block of Differentiation
Burel, S. A., Harakawa, N., Zhou, L., Pabst, T., Tenen, D. G., & Zhang, D. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.16.5577-5590.2001 · Cited by 140 · see citing works
Oncogenic tyrosine kinases and the dna-damage response
Skórski, T. (2002) · Nature reviews. Cancer · doi:10.1038/nrc799 · Cited by 136 · see citing works
CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes
Dik, W. A., Brahim, W., Braun, C., Asnafi, V., Dastugue, N., Bernard, O., van Dongen, J. J. M., Langerak, A. W., Macintyre, E. A., & Delabesse, É. (2005) · Leukemia · doi:10.1038/sj.leu.2403891 · Cited by 132 · see citing works
Deshpande, A. J., Cusan, M., Rawat, V. P. S., Reuter, H., Krause, A., Pott, C., Quintanilla‐Martínez, L., Kakadia, P. M., Kuchenbauer, F. C., Ahmed, F., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.023 · Cited by 126 · see citing works
Self-citationMechanisms of chromosome instability in cancers
Jefford, C. E., & Irminger‐Finger, I. (2006) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2006.02.005 · Cited by 125 · see citing works
Nakamura, K. M., Sakai, W., Kawamoto, T., Bree, R. T., Lowndes, N. F., Takeda, S., & Taniguchi, Y. (2006) · DNA repair · doi:10.1016/j.dnarep.2006.03.008 · Cited by 111 · see citing works
DiMartino, J. F., Miller, T., Ayton, P. M., et al. (2000) · Blood · doi:10.1182/blood.v96.12.3887 · Cited by 102 · see citing works
Bohlander, S. K., Muschinsky, V., Schrader, K., Siebert, R., Schlegelberger, B., Harder, L., Schemmel, V., Fonatsch, C., Ludwig, W., Hiddemann, W., et al. (2000) · Leukemia · doi:10.1038/sj.leu.2401614 · Cited by 97 · see citing works
Self-citationGenome-wide histone modifications: gaining specificity by preventing promiscuity
van Leeuwen, F., & Gottschling, D. E. (2002) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(02)00393-9 · Cited by 83 · see citing works
Beverloo, H. B., Coniat, M. L., Wijsman, J., et al. (1995) · PubMed · Cited by 81 · see citing works
The role of CALM–AF10 gene fusion in acute leukemia
Caudell, D. L., & Aplan, P. (2007) · Leukemia · doi:10.1038/sj.leu.2405074 · Cited by 80 · see citing works
Zhang, K., Siino, J. S., Jones, P. R., et al. (2004) · PROTEOMICS · doi:10.1002/pmic.200400819 · Cited by 73 · see citing works
Self-citationGame, J. C., Williamson, M. S., & Baccari, C. (2004) · Genetics · doi:10.1534/genetics.104.028613 · Cited by 71 · see citing works
Caudell, D. L., Zhang, Z., Chung, Y. J., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3749 · Cited by 71 · see citing works
The Role of Signal Transducer and Activator of Transcription Factors in Leukemogenesis
Sternberg, D., & Gilliland, D. G. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.10.124 · Cited by 67 · see citing works
Archangelo, L. F., Gläsner, J., Krause, A., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209438 · Cited by 63 · see citing works
Klebig, M. L., Wall, M. D., Potter, M. D., Rowe, E., Carpenter, D. A., & Rinchik, E. M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1432634100 · Cited by 62 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Hanahan D, Weinberg RA. The hallmarks of can- cer. Cell. 2000;100:57-70.
Cited by
Sorted by citations
Histone methylation: a dynamic mark in health, disease and inheritance
Greer, E. L., & Shi, Y. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3173 · Cited by 2,241 · see citing works
The roles of DNA, RNA and histone methylation in ageing and cancer
Michalak, E. M., Burr, M. L., Bannister, A. J., & Dawson, M. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0143-1 · Cited by 549 · see citing works
Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer.
Sulli, G., Di Micco, R., & di Fagagna, F. D. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3344 · Cited by 238 · see citing works
DOT1L and H3K79 Methylation in Transcription and Genomic Stability
Wood, K., Tellier, M., & Murphy, S. (2018) · Biomolecules · doi:10.3390/biom8010011 · Cited by 209 · see citing works
The histone methyltransferase Dot1/DOT1L as a critical regulator of the cell cycle
Kim, W., Choi, M., & Kim, J.-E. (2014) · Cell Cycle · doi:10.4161/cc.28104 · Cited by 121 · see citing works
- Authors
- Lin, Y.-H., Kakadia, P. M., Chen, Y., Li, Y.-Q., Deshpande, A. J., Buske, C., Zhang, K.-L., Zhang, Y., Xu, G.-L., & Bohlander, S. K.
- Affiliations
- Chinese Academy of Sciences (CN)
- Helmholtz Munich (DE)
- Mass Spectrometry Facility, Department of Biochemistry, School of Medicine, Loma Linda University, CA; and
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-07-16
- Volume
- 114
- Issue
- 3
- Pages
- 651-658
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2039014113
- Cited by
- 64
- References
- 50
- Citations by year
- 2026: 1 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 6 · 2013: 8 · 2012: 5
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB 684)
- National Natural Science Foundation of China
- Max-Planck-Gesellschaft
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- H3K79 methylation, DOT1L, chromosomal instability, chromosomal translocation, leukemia, epigenetic modifications, gamma-irradiation sensitivity, secondary chromosomal aberrations, malignant transformation, DNA-damaging agents, HOXA5
- MeSH terms
- Animals, Chromatin, Histones, Humans, Leukemia, Methylation, Methyltransferases, Histone-Lysine N-Methyltransferase, Transcription Factors, Tumor Cells, Cultured, Oncogene Proteins, Fusion, Chromosomal Instability, Epigenesis, Genetic, Mice
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