IDH1, Histone Methylation, and So Forth
Authors: Virginie Penard-Lacronique, Olivier A. Bernard
Journal: Cancer Cell (2016)

IDH mutants cause aberrant DNA and histone methylation and contribute to hematological and neural malignancies. In this issue of Cancer Cell, Inoue et al. describe a potential specific effect of IDH1 mutations that reduces Atm expression via inhibition of H3K9 demethylases, which may represent a first step toward cellular transformation. IDH mutants cause aberrant DNA and histone methylation and contribute to hematological and neural malignancies. In this issue of Cancer Cell, Inoue et al. describe a potential specific effect of IDH1 mutations that reduces Atm expression via inhibition of H3K9 demethylases, which may represent a first step toward cellular transformation. The identification of somatically mutated genes is not always enough to understand the mechanisms underlying cellular transformation. Isocitrate dehydrogenase (IDH) enzymes belong to the tricarboxylic acid (TCA) cycle and synthesize alpha-Ketoglutarate (αKG), an essential co-factor of many biochemical reactions, including those catalyzed by enzymes of the dioxygenase family. IDH1 is mutated in various human tumors, including myeloid and neural malignancies. In glioma, IDH1 mutation is associated with chromosomes 1 and 19 abnormalities, for unclear reasons, but perhaps due to altered DNA maintenance. IDH1 mutant proteins (essentially R132 substitution mutants) acquire the ability to catalyze the reduction of αKG to 2-hydroxyglutarate (2HG). Mutant IDH2 proteins (essentially R140 or R172 substitution mutants) have similar properties. Among many consequences of 2HG accumulation, competition with αKG results in the inhibition of virtually all enzymes of the dioxygenase family (for review, see Losman and Kaelin, 2013Losman J.A. Kaelin Jr., W.G. Genes Dev. 2013; 27: 836-852Crossref PubMed Scopus (431) Google Scholar). 2HG has pleiotropic consequences and also genome-wide effects on epigenetic marks (Figure 1, top panel). Indeed, detailed analyses of human samples established TET enzymes as important enzymes inhibited by this oncometabolite, resulting in loss of hydroxymethylated cytosine and hypermethylation phenotypes in both acute myeloid leukemia (AML) and glioma. Many other consequences of 2HG accumulation have been described, including inhibition of ALKBH, a dioxygenase involved in DNA maintenance (Wang et al., 2015Wang P. Wu J. Ma S. Zhang L. Yao J. Hoadley K.A. Wilkerson M.D. Perou C.M. Guan K.L. Ye D. Xiong Y. Cell Rep. 2015; 13: 2353-2361Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), and hyper-succinylation, resulting in mitochondrial dysfunction (Li et al., 2015Li F. He X. Ye D. Lin Y. Yu H. Yao C. Huang L. Zhang J. Wang F. Xu S. et al.Mol. Cell. 2015; 60: 661-675Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). The inhibition of histone demethylases has been experimentally demonstrated, but the precise consequences have not been determined. Inoue et al. now identify the Atm gene to be downregulated due to histone methylation and closing of the chromatin structure as a consequence of expressing an IDH1 mutant (Inoue et al., 2016Inoue S. Li W.Y. Tseng A. Beerman I. Elia A.J. Bendall S.C. Lemonnier F.o. Kron K.J. Cescon D.W. Hao Z. et al.Cancer Cell. 2016; 30 (this issue): 337-348Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Inoue et al. elegantly used CyTOF mass cytometry to identify differentially expressed proteins in the hematopoietic system of Idh1 (R132H) knockin (KI) mice, with respect to wild-type mice. They identified ATM as underexpressed in progenitor fractions, including those containing long-term hematopoietic stem cells (LT-HSCs). Further analyses revealed reduced numbers and dysfunction of LT-HSCs, together with a decrease of ATM expression, in aged (7–10 months) KI mice but not in young (3–4 months) animals. In addition, this low ATM expression is associated with an increase in DNA damage marks 53BP1 and γH2AX foci in mutant LT-HSCs, both spontaneously and after irradiation, which might trigger the development of myeloid malignancies in these mice. The authors identified the decreased ATM expression as being due to accumulation of methylated H3K9, a transcriptional repression epigenetic mark and closed chromatin structure at the Atm promoter. Low expression of ATM and of other DNA-damage repair-related genes are also specifically associated with IDH1 mutations in human AML. These features are not observed in TET-deficient conditions in mice or in humans. The results presented by Inoue et al. warrant further investigations. LT-HSCs have a specific way of dealing with DNA damage that differs from committed progenitors (Mohrin et al., 2010Mohrin M. Bourke E. Alexander D. Warr M.R. Barry-Holson K. Le Beau M.M. Morrison C.G. Passegué E. Cell Stem Cell. 2010; 7: 174-185Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar). Indeed, due to their essentially quiescent status, LT-HSCs use non-homologous end-joining mechanism, an error-prone DNA repair mechanism, low ATM levels would decrease the repair accuracy. In addition, DNA damage has been suggested to stimulate differentiation (Santos et al., 2014Santos M.A. Faryabi R.B. Ergen A.V. Day A.M. Malhowski A. Canela A. Onozawa M. Lee J.E. Callen E. Gutierrez-Martinez P. et al.Nature. 2014; 514: 107-111Crossref PubMed Scopus (141) Google Scholar), potentially accounting for the loss of LT-HSC numbers and functions in Idh1 KI mice. Although these observations need to be replicated in humans, they suggest that transformation can be triggered by accumulating mutations in a specific juncture (LT-HSCs expressing low level of ATM) that is lost once the cells differentiate and proliferate. Oxidized cytosine forms, generated by TET enzymes, have been associated with DNA damage and repair. TET deficiencies are also described to lead to DNA repair defects, but at more mature hematopoietic states, indicating that IDH1 and TET mutations might both affect DNA repair in different ways. It will be important to reproduce these observations in a neural context and to find out whether the IDH1 mutant cells are sensitive to DNA repair inhibitors, a "synthetic lethality" therapeutic opportunity. In AML, this would allow targeting mutant LT-HSCs. Defects in DNA maintenance may also have consequences upon IDH1 inhibitor treatment currently being tested in clinical settings; because the chromatin is closed, ATM expression may not be normally resumed after treatment restoring demethylase activity. One wonders why, specifically, ATM is downregulated in IDH1 mutant LT-HSCs. Obviously, inactivation of other tumor suppressors would also be effective in triggering cellular transformation. Besides DNA repair, ATM functionally interacts with many intracellular processes (Shiloh and Ziv, 2013Shiloh Y. Ziv Y. Nat. Rev. Mol. Cell Biol. 2013; 14: 197-210Crossref Scopus (1119) Google Scholar), including chromatin structure, nucleic acid and cellular metabolism, redox and mitochondrial homeostasis, and cell-cycle and intracellular signaling, and has an important role in neural biology. Whether these activities are affected by the drop in ATM expression, which is even more pronounced at the protein than at the RNA level, will have to be determined, as well as whether they play a role in cellular selection (see below). These observations also fit very well with the current data indicating that IDH1 mutations affect chromatin structure. DNA methylation induced by mutant IDH1 may deregulate chromatin organization and favor open chromatin structure, leading to oncogenic overexpression (Flavahan et al., 2016Flavahan W.A. Drier Y. Liau B.B. Gillespie S.M. Venteicher A.S. Stemmer-Rachamimov A.O. Suvà M.L. Bernstein B.E. Nature. 2016; 529: 110-114Crossref PubMed Scopus (748) Google Scholar); conversely, H3K9 methylation would close the chromatin structure, leading to repression of tumor suppressor (Inoue et al., 2016Inoue S. Li W.Y. Tseng A. Beerman I. Elia A.J. Bendall S.C. Lemonnier F.o. Kron K.J. Cescon D.W. Hao Z. et al.Cancer Cell. 2016; 30 (this issue): 337-348Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). How these modifications of chromatin structure would affect DNA repair is currently a matter of intensive investigation. Deregulation of chromatin organization, however, sets the conditions for cellular transformation, as schematized in Figure 1. KDM4 demethylases are responsible for H3K9 demethylation. They have been shown to target the H3K4me3-positive region, but it is not known how they are specifically recruited to the Atm promoter in normal condition. The recruitment of TET enzymes to DNA is likely a combination of interactions with each other, interactions with CpG, and recruitment by linage-specific transcription factors such as SPI1. As suggested from published analyses (including ours; Scourzic et al., 2016Scourzic L. Couronné L. Pedersen M.T. Della Valle V. Diop M. Mylonas E. Calvo J. Mouly E. Lopez C.K. Martin N. et al.Leukemia. 2016; 30: 1388-1398Crossref PubMed Scopus (55) Google Scholar) of mutants affecting the control of DNA (de)methylation, it is possible that even a modest deregulation of the control or a decrease in (de)methylation activity allows an epigenetic drift and selection of the best-fitted epigenetic clones. This would allow progressive clonal dominance of the mutant clone(s) in the hematopoietic system, followed by AML development. The authors want to thank Thomas Mercher and Filippo Rosseli for discussion and acknowledge the funding of INCa-DGOS-INSERM 6043 and INCa PLBIO. Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2Inoue et al.Cancer CellJuly 14, 2016In BriefAlthough strong evidence supports that IDH1 mutants act by inhibiting TET2 in hematological malignancies, there are clear clinical differences between mutations of these genes. Inoue et al. show that mutant IDH1 decreases ATM independent of TET2, leading to impaired DNA repair and reduced hematopoietic stem cells. Full-Text PDF Open ArchiveIDH1, Histone Methylation, and So ForthPenard-Lacronique et al.Cancer CellSeptember 12, 2016In Brief(Cancer Cell 30, 192–194; August 8, 2016) Full-Text PDF Open Archive