Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML
Abstract
Key Points: IDH1 promotes leukemogenesis in vivo in cooperation with HoxA9. Pharmacologic inhibition of mutant IDH1 efficiently inhibits AML cells of IDH1-mutated patients but not of normal CD34+ bone marrow cells.
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Overexpression of HOXA9 dysregulates MAPK signalling and collaborates with IDH1R132H to induce a short-latency AML in mice.
“in vivo transplantation experiments have shown that the overexpression of HOXA9 dysregulates MAPK signalling and collaborates with IDH1R132H to induce a short-latency AML in mice.9”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [9]
HOXA9 is frequently overexpressed in human AMLs, notably in patients harbouring the IDH1R132H mutation.
“The homeobox protein HOXA9 contributes to haematopoiesis and is frequently overexpressed in human AMLs,8 notably in patients harbouring the IDH1R132H mutation.9”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [9]
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“HMS-101 is a small-molecule inhibitor of mutant IDH1 which reduced 2-HG level, affected proliferation and the ERK (extracellular signal-regulated kinase) signaling pathway, and inhibited colony formation of IDH1-mut murine cells and primary AML cells cultured ex vivo without affecting normal bone marrow cells [77].”
BackgroundIsocitrate dehydrogenase inhibitors in acute myeloid leukemia
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“IDH1/2 mutated patients may benefit from new targeted therapies with specific molecules inhibiting of IDH1 or IDH2 mutant proteins [15–18].”
BackgroundVitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia
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“It was found that HMS-101 could significantly induce apoptosis in mIDH1 AML cells and mouse CD341 myeloid cells (Chaturvedi et al., 2013).”
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“Mutant IDH1 greatly accelerated the onset of myeloproliferative AML in mice in co-operation with the transcription factor HOXA9, which is involved in stem cell maintenance and hematopoietic differentiation, thus proving oncogenic potential (Argiropoulos & Humphries, 2007; Chaturvedi et al., 2013; Nakamura et al., 1996…”
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“through induction of differentiation and apoptosis in IDH mutant leukemia cell lines.(76,77) This has led to the initiation of early phase clinical trials targeting specific IDH1/2 mutants (Table 1).”
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“Several other IDH mutation inhibitor candidates have shown promising efficacy in preclinical studies and AML clinical trials, including MRK-A [146], FT-2102 (Olutasidenib) [147], HMS-101 [148], and IDH305 [149] (a summary of IDH mutation inhibitors is available in Table 2).”
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“Gain of function mutations in IDH1/2 convert a-ketoglutarate into 2-hydroxyglutarate [5], which inhibits demethylating enzymes resulting in histone and DNA hypermethylation [6].”
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“Specifically, high levels of the well-known oncometabolite 2-hydroxyglutarate (a product of IDH1/IDH2 mutations) were detected in AML patients with poor prognosis, suggesting its potential role as a prognostic marker [96].”
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“This is consistent with data showing that mutant IDH1/2 expression in mice doesn’t result in enhanced HSC self-renewal (38,41) and with Trissal et al.”
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“Since Hox genes frequently have increased expression associated with IDH-mutated AML, HoxA9 andmutant IDH1were retrovirally transduced in a murine bonemarrowmodel and amyeloproliferative phenotypewas seenwith increased cell cycling, decreased CDK gene expression, and increased mitogen-activated protein kinase activity…”
BackgroundPrecision Oncology Beyond Genomics: The Future Is Here—It Is Just Not Evenly Distributed
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BackgroundThe role of mutations in epigenetic regulators in myeloid malignancies
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“Treating glioma cells with AGI-5198 reduced H3K9 methylation levels and induced consequent gene expression changes which promoted differentiation and decreased cell growth (139).”
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“Nat Rev Drug Discov (2006) 5(9):769–84.”
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“4, 17 Interestingly, clonal hematopoiesis of indeterminate potential (CHIP) driven by leukemia-associated gene mutations has been associated with all-cause mortality due to an increased risk of coronary artery disease (CAD) 18, 19 and heart failure.”
Self-citationEpigenetic regulators as promising therapeutic targets in acute myeloid leukemia
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Biochemical, Epigenetic, and Metabolic Approaches to Target IDH Mutations in Acute Myeloid Leukemia
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“(18, 19) We found that mutant IDH1 is frequently associated with high expression of HOXA and HOXB cluster genes in AML patients and co-expression of mutant IDH1 with HoxA9 in mouse bone marrow cells induced a rapid monocytic leukemia in mice.”
InfluentialSelf-citationEpigenetic regulators and their impact on therapy in acute myeloid leukemia
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Glial Progenitors as Targets for Transformation in Glioma
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“However, pioneering studies in leukemia demonstrated that IDH mutation leads to a block in differentiation in hemapoietic precursor cells (Chaturvedi et al., 2013).”
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Action at a Distance: Allostery and the Development of Drugs to Target Cancer Cell Metabolism
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“Recently IDH1 mutations have been targeted [33], and mutationspecific treatments are currently the aim of a phase I clinical trial that includes cholantiocarcinomas (http:// clinicaltrial.gov/ct2/show/NCT02073994).”
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“Median age (range), years 62 (51-70) 50 (22-60) 54 (22-70)”
Enasidenib and ivosidenib in AML
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Visualization of Diagnostic and Therapeutic Targets in Glioma With Molecular Imaging
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“Preclinical data indicated early on that targeted inhibition of both IDH1 and IDH2 blocked colony formation of AML cells from IDH1-mutated patients and induced differentiation (91, 92).”
BackgroundChaturvedi, A., Gupta, C., Gabdoulline, R. R., Borchert, N. M., Goparaju, R., Kaulfuß, S., Görlich, K., Schottmann, R., Othman, B., Welzenbach, J., et al. (2020) · Haematologica · doi:10.3324/haematol.2019.236992 · Cited by 37 · see citing works
Self-citationIDH Signalling Pathway in Cholangiocarcinoma: From Biological Rationale to Therapeutic Targeting
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“Indeed, iCCA cells often have higher levels of total ERK 1 and 2, phospho-ERK 1 and 2, and a downstream target, phospho-CREB [58].”
BackgroundMechanistic aspects of epigenetic dysregulation in SLE
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“recently reported that a small molecular inhibitor targeting mutant IDH1 induced apoptosis and decreased colony formation in methylcellulose of IDH1-mutant human primary bone marrow cells [47].”
BackgroundThe mechanistic role of DNA methylation in myeloid leukemogenesis
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“Moreover, HOXA9 is overexpressed in IDH1-mutated AML patients and IDH1 mutants cooperate with HOXA9 to induce leukaemia in mice (Chaturvedi et al, 2013).”
BackgroundEpigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases
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“Similarly, HMS101 inhibitor limits the growth of acute myeloid leukemia cells suggesting potential therapeutic application of TET inhibitors in cancer and also in rheumatic diseases [21].”
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“Improvement in our knowledge of gene mutations in AML has further complicated the baseline prognostic assessment of these patients, that should now include FLT3, NPM1, CEBPA, as well as RUNX1, DNMT3A, IDH1, IDH2, TET2, ASXL1 and TP53 [2,3].”
BackgroundInfluentialOrphan drug designation for pracinostat, volasertib and alvocidib in AML
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“may be a promising therapeutic target in human AML cells [26].”
BackgroundThe Yin and Yang of cancer genes
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Rational Combinations of Targeted Agents in AML
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“Recent approaches have involved exploring new therapeutic targets, e.g., isocitrate dehydrogenase (IDH) [12] or immune checkpoints, delivering conventional cytotoxic agents in fixed molar ratios [13,14], harnessing the power of T-cells against AML stem cell antigens (e.g., CD123) using dual…”
Bravo, G. M., Lee, E., Merchán, B., Kantarjian, H. M., & Garcia‐Manero, G. (2014) · British Journal of Haematology · doi:10.1111/bjh.12957 · Cited by 30 · see citing works
“The presence of mutant IDH genes, especially in heterozygous cases, induces HOXA9 genes, promotes cell-cycle transition through CDKN2A and CDKN2B epigenetic silencing, and activates different signalling pathways, such as MAPK (Chaturvedi et al, 2013).”
BackgroundInfluential
- Authors
- Chaturvedi, A., Araujo Cruz, M. M., Jyotsana, N., Sharma, A., Yun, H., Görlich, K., Wichmann, M., Schwarzer, A., Preller, M., Thol, F., Meyer, J., Haemmerle, R., Struys, E. A., Jansen, E. E., Modlich, U., Li, Z., Sly, L. M., Geffers, R., Lindner, R., Manstein, D. J., Lehmann, U., Krauter, J., Ganser, A., & Heuser, M.
- Affiliations
- Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation,
- Institute of Experimental Hematology, and
- Medizinische Hochschule Hannover (DE)
- Vrije Universiteit Amsterdam (NL)
- University of British Columbia (CA)
- Helmholtz Centre for Infection Research (DE)
- Institute of Cell Biology (UA)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2013-10-17
- Volume
- 122
- Issue
- 16
- Pages
- 2877-2887
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2071370702
- Cited by
- 210
- References
- 45
- Citations by year
- 2026: 2 · 2025: 14 · 2024: 9 · 2023: 7 · 2022: 8 · 2021: 15 · 2020: 18 · 2019: 14 · 2018: 19 · 2017: 23 · 2016: 18 · 2015: 26 · 2014: 35 · 2013: 2
- FWCI
- 19.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH1 mutation, isocitrate dehydrogenase, acute myeloid leukemia, leukemogenesis, 2-hydroxyglutarate, HOXA9, myeloproliferative neoplasms, CDKN2A, CDKN2B, MAPK signaling, IDH1 inhibitor, therapeutic target
- MeSH terms
- Adolescent, Adult, Animals, Cell Cycle, Female, Humans, Isocitrate Dehydrogenase, Mice, Inbred C57BL, Middle Aged, Mutation, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Bone Marrow Transplantation, Apoptosis, Antigens, CD34, MAP Kinase Signaling System, Mice, Young Adult
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