The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
Open accessAbstract
Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.
Overview
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
Verification
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?
In the citing paper
“Furthermore, a knock-in of a mutant IDH1 allele into normal hematopoietic cells and into chondrocytes in vivo triggers an aberrant expansion of targeted cell lineages (Hirata et al., 2015; Sasaki et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Sasaki et al., 2012
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829
The control of the false discovery rate in multiple testing under dependency
Benjamini, Y., & Yekutieli, D. (2001) · The Annals of Statistics · doi:10.1214/aos/1013699998 · Cited by 10,490
Statistical significance for genomewide studies
Storey, J. D., & Tibshirani, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1530509100 · Cited by 9,692
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications
Krueger, F., & Andrews, S. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr167 · Cited by 5,275
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Self-citationXu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
Self-citationIdentification of a CpG Island Methylator Phenotype that Defines a Distinct Subgroup of Glioma
Noushmehr, H., Weisenberger, D. J., Diefes, K., Phillips, H. S., Pujara, K., Berman, B. P., Pan, F., Pelloski, C. E., Sulman, E. P., Bhat, K. P., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.03.017 · Cited by 2,337
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219
Conditional gene targeting in macrophages and granulocytes using LysMcre mice
Clausen, B. E., Burkhardt, C., Reith, W., Renkawitz, R., & Förster, I. (1999) · Transgenic Research · doi:10.1023/a:1008942828960 · Cited by 2,098
lumi : a pipeline for processing Illumina microarray
Du, P., Kibbe, W. A., & Lin, S. M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn224 · Cited by 2,028
The UCSC Genome Browser database: update 2011
Fujita, P. A., Rhead, B., Zweig, A. S., Hinrichs, A. S., Karolchik, D., Cline, M., Goldman, M. J., Barber, G. P., Clawson, H., Coelho, A., et al. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq963 · Cited by 1,843
FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.003 · Cited by 1,562
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., Ohmura, M., Naka, K., Hosokawa, K., Ikeda, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1388 · Cited by 1,362
Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis
Meissner, A. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki901 · Cited by 1,261
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Zhao, S., Lin, Y., Xu, W., Jiang, W., Zha, Z., Wang, P., Yu, W., Li, Z., Gong, L., Peng, Y., et al. (2009) · Science · doi:10.1126/science.1170944 · Cited by 1,119
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035
Transgenic mice with hematopoietic and lymphoid specific expression of Cre
de Boer, J., Williams, A., Skavdis, G., Harker, N., Coles, M., Tolaini, M., Norton, T., Williams, K., Roderick, K., Potocnik, A. J., et al. (2003) · European Journal of Immunology · doi:10.1002/immu.200310005 · Cited by 739
Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.
Goardon, N., Marchi, E., Atzberger, A., Quek, L., Schuh, A., Soneji, S., Woll, P., Mead, A., Alford, K., Rout, R., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.012 · Cited by 671
Munger, J. C., Bennett, B. D., Parikh, A., Feng, X., McArdle, J., RABITZ, H. A., Shenk, T. E., & Rabinowitz, J. D. (2008) · Nature Biotechnology · doi:10.1038/nbt.1500 · Cited by 641
Self-citationBajad, S. U., Lu, W., Kimball, E., Yuan, J., Peterson, C. N., & Rabinowitz, J. D. (2006) · Journal of Chromatography A · doi:10.1016/j.chroma.2006.05.019 · Cited by 593
The hematopoietic stem cell niche: Low in oxygen but a nice place to be
Eliasson, P., & Jönsson, J. (2009) · Journal of Cellular Physiology · doi:10.1002/jcp.21908 · Cited by 499
A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia
Klinakis, A., Lobry, C., Abdel-Wahab, O. I., Oh, P., Haeno, H., Buonamici, S., de Walle, I. V., Cathelin, S., Trimarchi, T., Araldi, E., et al. (2011) · Nature · doi:10.1038/nature09999 · Cited by 400
Akalin, A., Garrett-Bakelman, F. E., Kormaksson, M., Busuttil, J., Zhang, L., Khrebtukova, I., Milne, T. A., Huang, Y., Biswas, D., Hess, J. L., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002781 · Cited by 296
Self-citationThe OP9-DL1 System: Generation of T-Lymphocytes from Embryonic or Hematopoietic Stem Cells In VitroPreprint
Holmes, R. B., & Zúñiga‐Pflücker, J. C. (2009) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot5156 · Cited by 206
Self-citationCallens, C., Coulon, S., Naudin, J., Radford-Weiss, I., Boissel, N., Raffoux, E., Wang, P. H. M., Agarwal, S., Tamouza, H., Paubelle, E., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20091488 · Cited by 197
Ye, M., Iwasaki, H., Laiosa, C. V., Stadtfeld, M., Xie, H., Heck, S., Clausen, B. E., Akashi, K., & Graf, T. (2003) · Immunity · doi:10.1016/s1074-7613(03)00299-1 · Cited by 194
Acute Myeloid Leukemia With IDH1 or IDH2 Mutation
Patel, K. P., Ravandi, F., Ma, D., Paladugu, A. V., Barkoh, B. A., Medeiros, L. J., & Luthra, R. (2010) · American Journal of Clinical Pathology · doi:10.1309/ajcpd7nr2rmnqdvf · Cited by 179
Patnaik, M. M., Hanson, C. A., Hodnefield, J. M., Lasho, T. L., Finke, C. M., Knudson, R. A., Ketterling, R. P., Pardanani, A. D., & Tefferi, A. (2011) · Leukemia · doi:10.1038/leu.2011.298 · Cited by 147
Complex and Context Dependent Regulation of Hematopoiesis by TGF‐β Superfamily Signaling
Söderberg, S. S., Karlsson, G., & Karlsson, S. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04569.x · Cited by 113
Signal control of hematopoietic stem cell fate: Wnt, Notch, and Hedgehog as the usual suspects
Campbell, C. J. V., Risueño, R. M., Salati, S., Guezguez, B., & Bhatia, M. (2008) · Current Opinion in Hematology · doi:10.1097/moh.0b013e328303b9df · Cited by 51
Self-renewal related signaling in myeloid leukemia stem cells
Heidel, F. H., Mar, B., & Armstrong, S. (2011) · International journal of hematology · doi:10.1007/s12185-011-0901-0 · Cited by 48
Flagged first, then by citations
Cited by
Sorted by citations
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926
Modulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579
Self-citationWallace, D. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3365 · Cited by 2,404
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,369
Epigenetic Determinants of CancerPreprint
Baylin, S. B., & Jones, P. A. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019505 · Cited by 1,414
Metadata
- Authors
- Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brüstle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., You-Ten, A., Li, W. Y., Schalm, S., Su, S. M., Virtanen, C., Reifenberger, G., Ohashi, P. S., Barber, D. L., Figueroa, M. E., Melnick, A., Zúñiga-Pflücker, J.-C., & Mak, T. W.
- Affiliations
- University Health Network (CA)
- University of Rochester Medicine (US)
- University of Toronto (CA)
- Agios Pharmaceuticals (United States) (US)
- Heinrich Heine University Düsseldorf (DE)
- Cornell University (US)
- Corresponding author
- Mak, Tak W.
- ORCID
- Venue
- Nature
- Published
- 2012-07-04
- Volume
- 488
- Issue
- 7413
- Pages
- 656-659
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4005896
- OpenAlex
- W2035409103
- Cited by
- 513
- References
- 34
- Citations by year
- 2026: 5 · 2025: 20 · 2024: 16 · 2023: 27 · 2022: 26 · 2021: 31 · 2020: 28 · 2019: 34 · 2018: 33 · 2017: 44 · 2016: 55 · 2015: 55 · 2014: 53 · 2013: 64 · 2012: 21
- FWCI
- 41.37
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute of Allergy and Infectious Diseases (R56AI081773, R01AI081773)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- IDH1 R132H mutation, isocitrate dehydrogenase, 2-hydroxyglutarate, acute myeloid leukemia, hematopoietic progenitor cells, epigenetics, DNA methylation, histone methylation, conditional knock-in mice, extramedullary hematopoiesis, splenomegaly, anemia
- MeSH terms
- Aging, Animals, Bone Marrow, Disease Models, Animal, Female, Glioma, Hematopoiesis, Hematopoietic Stem Cells, Histones, Humans, Isocitrate Dehydrogenase, Male, Mutation, Spleen, Leukemia, Myeloid, Acute, CpG Islands, Cell Lineage, DNA Methylation, Myeloid Cells, Epigenesis, Genetic, Mutant Proteins, Mice, Gene Knock-In Techniques
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
