The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia
Open accessAbstract
Key Points: Pinometostat demonstrates first evidence of DOT1L target inhibition and clinical responses in a subset of MLL-r advanced leukemia patients. The observed safety profile of pinometostat shows potential for exploration of combination therapies in leukemia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma.
“More recently, the arginine methyltransferase PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma 171-178 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [175]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Golub, T. R., Slonim, D. K., Tamayo, P., Huard, C., Gaasenbeek, M., Mesirov, J. P., Coller, H., Loh, M. L., Downing, J. R., Caligiuri, M. A., et al. (1999) · Science · doi:10.1126/science.286.5439.531 · Cited by 11,516 · see citing works
Byrd, J. C. (2002) · Blood · doi:10.1182/blood-2002-03-0772 · Cited by 1,594 · see citing works
Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., Levine, J. E., Wang, J., Hahn, W. C., Gilliland, D. G., et al. (2006) · Nature · doi:10.1038/nature04980 · Cited by 1,513 · see citing works
Self-citationMLL translocations, histone modifications and leukaemia stem-cell development
Krivtsov, A., & Armstrong, S. (2007) · Nature Reviews. Cancer · doi:10.1038/nrc2253 · Cited by 1,294 · see citing works
Self-citationMLL Targets SET Domain Methyltransferase Activity to Hox Gene Promoters
Milne, T. A., Briggs, S. D., Brock, H. W., Martin, M. E., Gibbs, D. Y., Allis, C. D., & Hess, J. L. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00741-4 · Cited by 1,051 · see citing works
Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor
Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Majer, C. R., Sneeringer, C. J., Song, J. J., Johnston, L. D., Scott, M. P., Smith, J. J., Xiao, Y., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.009 · Cited by 926 · see citing works
Self-citationMLL-rearranged Leukemia is Dependent on Aberrant H3K79 Methylation by DOT1L
Bernt, K., Zhu, N., Sinha, A., Vempati, S., Faber, J., Krivtsov, A., Feng, Z.-H., Punt, N., Daigle, A., Bullinger, L., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.010 · Cited by 896 · see citing works
Self-citationhDOT1L 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
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia
Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Basavapathruni, A., Jin, L., Boriack-Sjodin, P. A., Allain, C. J., Klaus, C. R., Raimondi, A., Scott, M. P., et al. (2013) · Blood · doi:10.1182/blood-2013-04-497644 · Cited by 722 · see citing works
Self-citationNakamura, T., Mori, T., Tada, S., Krajewski, W. A., Rozovskaia, T., Wassell, R. P., DuBois, G. C., Mazo, A., Croce, C. M., & Canaani, E. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00740-2 · Cited by 720 · 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
Self-citationSecondary leukemias induced by topoisomerase-targeted drugs
Felix, C. A. (1998) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(98)00139-0 · Cited by 415 · see citing works
A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification
Mueller, D., Bach, C., Zeisig, D. T., García-Cuéllar, M.-P., Monroe, S., Sreekumar, A., Zhou, R., Nesvizhskii, A. I., Chinnaiyan, A. M., Hess, J. L., et al. (2007) · Blood · doi:10.1182/blood-2007-05-090514 · Cited by 396 · see citing works
Schoch, C., Schnittger, S., Klaus, M., et al. (2003) · Blood · doi:10.1182/blood-2003-02-0434 · Cited by 353 · see citing works
The Pathogenesis of Mixed-Lineage Leukemia
Muntean, A. G., & Hess, J. L. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011811-132434 · Cited by 347 · see citing works
Disruptor 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
DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis.
Nguyen, A., Taranova, O., He, J.-Q., & Zhang, Y. (2011) · Blood · doi:10.1182/blood-2011-02-334359 · Cited by 280 · see citing works
Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia
Drabkin, H., Parsy, C., Ferguson, K., Guilhot, F., Lacotte, L., Roy, L., Zeng, C. X., Barón, A. E., Hunger, S. P., Varella-Garcia, M., et al. (2002) · Leukemia · doi:10.1038/sj.leu.2402354 · Cited by 185 · see citing works
Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality
Rozovskaia, T., Feinstein, E., Mor, O., Foà, R., Blechman, J. A., Nakamura, T., Croce, C. M., Cimino, G. G., & Canaani, E. (2001) · Oncogene · doi:10.1038/sj.onc.1204174 · Cited by 181 · see citing works
Leukemic transformation by the MLL-AF6 fusion oncogene requires the H3K79 methyltransferase Dot1l
Deshpande, A. J., Chen, L., Fazio, M., Sinha, A. U., Bernt, K. M., Banka, D., Dias, S., Chang, J. C.-C., Olhava, E. J., Daigle, S. R., et al. (2013) · Blood · doi:10.1182/blood-2012-11-465120 · Cited by 173 · see citing works
Self-citationHistone H3 Lysine 79 Methyltransferase Dot1 Is Required for Immortalization by MLL Oncogenes
Chang, M.-J., Wu, H., Achille, N. J., Reisenauer, M. R., Chou, C.-W., Zeleznik‐Le, N. J., Hemenway, C. S., & Zhang, W. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-3294 · Cited by 173 · see citing works
Ayton, P. M., Chen, E. H., & Cleary, M. L. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.23.10470-10478.2004 · Cited by 160 · see citing works
HOX expression patterns identify a common signature for favorable AML
Andreeff, M., Ruvolo, V. R., Gadgil, S., Zeng, C., Coombes, K. R., Chen, W., Kornblau, S. M., Barón, A. E., & Drabkin, H. A. (2008) · Leukemia · doi:10.1038/leu.2008.198 · Cited by 148 · see citing works
Chen, L., Deshpande, A. J., Banka, D., Bernt, K. M., Dias, S., Buske, C., Olhava, E. J., Daigle, S. R., Richon, V. M., Pollock, R. M., et al. (2012) · Leukemia · doi:10.1038/leu.2012.327 · Cited by 130 · see citing works
Self-citationDeregulation of the HOXA9/MEIS1 axis in acute leukemia
Collins, C. T., & Hess, J. L. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000245 · Cited by 130 · see citing works
Klaus, C. R., Iwanowicz, D., Johnston, D., Campbell, C. T., Smith, J. J., Moyer, M. P., Copeland, R. A., Olhava, E. J., Scott, M. P., Pollock, R. M., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.214577 · Cited by 128 · see citing works
Self-citationDOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia
Rau, R. E., Rodriguez, B. A. T., Luo, M., Jeong, M., Rosen, A., Rogers, J. H., Campbell, C. T., Daigle, S. R., Deng, L., Song, Y., et al. (2016) · Blood · doi:10.1182/blood-2015-11-684225 · Cited by 128 · see citing works
Self-citationTargeting DOT1L and HOX Gene Expression in MLL-Rearranged Leukemia and Beyond
Chen, C., & Armstrong, S. (2015) · Experimental Hematology · doi:10.1016/j.exphem.2015.05.012 · Cited by 121 · see citing works
Self-citation11q23/MLL Acute Leukemia : Update of Clinical Aspects
Tamai, H., & Inokuchi, K. (2010) · Journal of the Japan Society of the Reticuloendothelial System · doi:10.3960/jslrt.50.91 · Cited by 90 · see citing works
Tsutsumi, S., Taketani, T., Nishimura, K., Ge, X., Taki, T., Sugita, K., Ishii, E., Hanada, R., Ohki, M., Aburatani, H., et al. (2003) · PubMed · Cited by 81 · see citing works
Basavapathruni, A., Olhava, E. J., Daigle, S. R., Therkelsen, C. A., Jin, L., Boriack‐Sjodin, P. A., Allain, C. J., Klaus, C. R., Raimondi, A., Scott, M. P., et al. (2014) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.1889 · Cited by 79 · see citing works
Self-citationMixed lineage rearranged leukaemia
Stein, E. M., & Tallman, M. S. (2015) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000123 · Cited by 69 · see citing works
Self-citationMLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition
Kühn, M. W. M., Hadler, M., Daigle, S. R., Koche, R. P., Krivtsov, A. V., Olhava, E. J., Caligiuri, M. A., Huang, G., Bradner, J. E., Pollock, R. M., et al. (2015) · Haematologica · doi:10.3324/haematol.2014.115337 · Cited by 54 · see citing works
Self-citationWaters, N. J., Daigle, S. R., Rehlaender, B. N., Basavapathruni, A., Campbell, C. T., Jensen, T. B., Truitt, B. F., Olhava, E. J., Pollock, R. M., Stickland, K., et al. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.09.023 · Cited by 28 · see citing works
Self-citationGarrido, S. M., Bryant, E. M., & Appelbaum, F. R. (2000) · Leukemia Research · doi:10.1016/s0145-2126(00)00011-4 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
High-resolution characterization of gene function using single-cell CRISPR tiling screen
Yang, L., Chan, A. K. N., Miyashita, K., Delaney, C. D., Wang, X., Li, H., Pokharel, S. P., Li, S., Li, M., Xu, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24324-0 · Cited by 45 · see citing works
Self-citationHistone methyltransferase KMT2A: developmental regulation to oncogenic transformation
Ogino, J., & Dou, Y. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107791 · Cited by 21 · see citing works
- Authors
- Stein, E. M., Garcia-Manero, G., Rizzieri, D. A., Tibes, R., Berdeja, J. G., Savona, M. R., Jongen-Lavrenic, M., Altman, J. K., Thomson, B., Blakemore, S. J., Daigle, S. R., Waters, N. J., Suttle, A. B., Clawson, A., Pollock, R., Krivtsov, A., Armstrong, S. A., DiMartino, J., Hedrick, E., Löwenberg, B., & Tallman, M. S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
- Duke Medical Center (US)
- Mayo Clinic in Arizona (US)
- Sarah Cannon Research Institute, Nashville, TN;
- Vanderbilt-Ingram Cancer Center (US)
- Erasmus University Medical Center, Rotterdam, The Netherlands;
- Northwestern University (US)
- Epizyme (United States) (US)
- Dana-Farber Cancer Institute (US)
- Celgene, San Francisco, CA
- Erasmus MC (NL)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2018-06-14
- Volume
- 131
- Issue
- 24
- Pages
- 2661-2669
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6265654
- OpenAlex
- W2802129476
- Cited by
- 461
- References
- 35
- Citations by year
- 2026: 33 · 2025: 41 · 2024: 65 · 2023: 60 · 2022: 59 · 2021: 72 · 2020: 61 · 2019: 56 · 2018: 11 · 2013: 1
- FWCI
- 36.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- National Cancer Institute (P30CA008748, P01CA066996)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- DOT1L inhibition, H3K79 methylation, adult acute leukemia, histone methyltransferase inhibitors, drug safety, combination therapy
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Benzimidazoles, Female, Histones, Humans, Male, Methylation, Methyltransferases, Middle Aged, Histone-Lysine N-Methyltransferase, Leukemia, Myeloid, Acute, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
