scholarly journals Isocitrate Dehydrogenase 1 Mutant Cancers Are Metabolically Vulnerable to Inhibition of Acetyl CoA Carboxylase Via a 2-Hydroxyglutarate Independent Mechanism

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1054-1054
Author(s):  
Daniel Thomas ◽  
Subarna Sinha ◽  
Steven M. Chan ◽  
Manhong Wu ◽  
Damoun Torabi ◽  
...  
Keyword(s):  
Cell Growth ◽  
De Novo ◽  
Idh1 Mutation ◽  
Computational Method ◽  
Isocitrate Dehydrogenase 1 ◽  
Synthetic Lethal ◽  
Idh1 R132h ◽  
Malonyl Coa ◽  
Mutant Idh1 ◽  
Pan Cancer

Abstract Introduction: Mutations substituting arginine 132 of isocitrate dehydrogenase 1 (IDH1) are recurrent in acute myeloid leukemia (AML) and several other cancers, resulting in the aberrant production of the onco-metabolite, R-2-hydroxyglutarate (2-HG), as well as an inability to convert cytoplasmic alpha-ketoglutarate to isocitrate via reductive carboxylation. Currently, small molecules that effectively inhibit the neomorphic enzyme and abrogate the production of 2-HG, such as AG-120, are in clinical trials with promising results. However, these inhibitors have not proven to be curative in most AML cases, indicating a need for additional targeted therapies. We have previously investigated synthetic lethal vulnerabilities in IDH1-mutated AML and identified an interaction with BCL2 leading to increased susceptibility to ABT-199 (Chan et al, 2015). Synthetic lethal approaches targeting 2-HG independent metabolic vulnerabilities conferred by mutant IDH1 may complement IDH1 mutant inhibitors. Using a novel computational method (MiSL) based on Boolean implication (if-then rules) mining of pan-cancer data, we identified acetyl CoA carboxylase (ACACA) as a potential druggable target in IDH1-mutated AML. ACACA is the rate-limiting step in the de novo synthesis of fatty acids, and mutant IDH1 leads to a reduction in malonyl-CoA, a key building block for fatty acids, in a 2-HG independent manner. This finding led us to investigate a potential synthetic lethal interaction between mutant IDH1 and ACACA based on the hypothesis that the combination causes marked inhibition of fatty acid synthesis required for cell growth. Methods: Boolean implications (MiSL) were used to identify candidate synthetic lethal interactions with mutant IDH1 by isolating genes deleted only in the absence of the mutation and with differential gene expression within pan-cancer TCGA data. Validation was performed using THP-1 cells transduced with doxycycline-inducible wildtype and R132H mutant IDH1 lentiviral vectors, and primary patient IDH1-mutant and wildtype AML samples, using both shRNAs and a targeted pharmacologic inhibitor of ACACA. Metabolomics was performed using semi-targeted mass spectrometry and liquid chromatography. Finally, primary AML samples and IDH1-mutant and wildtype cancer cell lines (HT-1080, U118, U87) were transduced with validated shRNA and engrafted into NSG mice. Results: Our computational method found that IDH1 mutation and ACACA deletions were mutually exclusive in pan-cancer TCGA data, ACACA deletions resulted in lowered expression of ACACA, and ACACA was differentially over-expressed in IDH1-mutant AML compared to IDH1-wildtypeAML. Pharmacologic inhibition of ACACA with 2 uM TOFA caused a marked reduction in cell growth in the presence of IDH1 R132H (+ dox), but not in its absence (- dox; p = 0.0001). Similarly, knockdown of ACACA with independent shRNAs caused a defect in viable cell growth in the presence of IDH1 R132H (+ dox), but not in its absence (- dox) or with scrambled shRNA (p=0.009, shRNA #1 vs. scrambled; p=0.01, shRNA #2 vs. scrambled). Primary IDH1 R132 mutated purified AML blasts were selectively sensitive to TOFA treatment compared to IDH1 wildtype normal karyotype blasts (IC50 0.6 uM vs 6 uM, p=0.009) in viable growth assays. Furthermore, when transduced with lentivirus encoding shRNA to ACACA, primary IDH1-mutant AML cells exhibited markedly reduced engraftment of RFP-positive human CD45+CD33+ leukemic cells compared to scrambled non-targeting shRNA (p < 0.05, Mann-Whitney U). As predicted, IDH1-mutant AML blasts pre-treated with 10uM AG-120 (sufficient to inhibit production of detectable 2-HG) remained susceptible to ACACA inhibition in vitro. Strikingly, in vivo models of IDH1 R132C mutated, but not wildtype, sarcoma cell lines exhibited a dramatic decrease in cell growth after ACACA inhibition that was not reversible by treatment with AG-120. Finally, metabolomic profiling revealed a major perturbation in multiple phospholipid fatty acid species and decreased malonyl-CoA conferred by IDH1 R132H, consistent with our proposed mechanism. Conclusion: We have identified de novo lipogenesis through ACACA as a critical metabolic vulnerability linked to IDH1 mutation in AML and provide evidence that therapeutic inhibition of ACACA with small molecules may be beneficial in AML, as well as in other cancers with IDH1 mutations. Disclosures Majeti: Forty Seven Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals IDH1 Mutant AML Is Susceptible to Targeting De Novo Lipid Synthesis Independent of 2-Hydroxyglutarate and Has a Distinct Metabolic Profile from IDH2 Mutant AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 440-440
Author(s):  
Daniel Thomas ◽  
Yusuke Nakauchi ◽  
Manhong Wu ◽  
Ming Zheng ◽  
Subarna Sinha ◽  
...  
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Lipid Synthesis ◽  
Idh1 Mutation ◽  
Idh1 R132h ◽  
Lipid Metabolites ◽  
Mutant Idh1 ◽  
Idh2 Mutation

Abstract Introduction: Mutations in IDH1 and IDH2 are recurrent in AML and several other cancers, resulting in the aberrant production of the onco-metabolite, R-2-hydroxyglutarate (2-HG), as well as an inability of mutant IDH1 to convert cytoplasmic alpha-ketoglutarate to isocitrate via reductive carboxylation. Currently, inhibitors of the neomorphic enzymes that abrogate the production of 2-HG, such as AG-120, are FDA-approved, but are not curative. Using a novel computational method (MiSL), we identified acetyl CoA carboxylase (ACACA) as a potential druggable target specifically in IDH1-mutated AML. ACACA regulates the de novo synthesis of lipid precursors by converting acetyl CoA to malonyl CoA building blocks. We hypothesize that IDH1 mutant AML exhibits a defect in reductive carboxylation and de novo fatty acid synthesis conferring preferential susceptibility to ACACA inhibition. Here, we investigate this hypothesis by comprehensively quantifying the metabolic landscape, including non-polar lipid metabolites, conferred by IDH1 R132H mutation compared to IDH2 mutation in isogenic cell lines and primary samples. Moreover, we investigate the in vitro and in vivo effects of targeting de novo lipid synthesis on IDH1 and IDH2 mutant AML. Methods: Comprehensive metabolomic profiling of primary FACS-purified AML blasts was performed using an in-house protocol optimised for extraction of non-polar lipid metabolites from less than 1 million primary cells. CD33+CD45+ leukemic blasts were profiled from 17 patient samples with IDH1 mutation (n=6), IDH2 mutation (n=5), or IDH1/2 wildtype (n=6) after culturing in serum-free media. 6 independent cord-blood CD34+ cells were profiled as a negative control. For validation of IDH1-specific effects, isogenic THP-1 cells transduced with doxycycline-inducible wildtype and R132H mutant IDH1 or R140Q mutant and wildtype IDH2 were profiled. Molecules were identified according to their molecular weight and retention time using Mass Hunter software (Agilent) and the Human Metabolome Database. For in vivo studies, primary AML samples were engrafted in NSG mice that were subjected to dietary modification with low lipid diet and/or treatment with selective inhibitors of ACACA and mutant IDH1. Results: Principle component analysis of metabolite abundance of 1400 unique compounds revealed striking differences between IDH1 and IDH2 mutant AML. Both IDH1 and IDH2 mutant samples produced high levels of 2-HG compared to wildtype AML and CD34+ cells (50 fold increase, P=4.5E-05). A major perturbation in multiple phospholipid fatty acid species was conferred by IDH1 R132H, but not by IDH2 mutation. The same pattern was observed in cell lines with 49 lipid species decreased in the presence of mutant IDH1 compared to only 2 perturbed with mutant IDH2. Direct comparison of IDH1 vs IDH2 mutant primary samples revealed 54 lipid metabolites significantly down-regulated in IDH1 mutant blasts (adjusted P value <0.05). To investigate the effects of targeting de novo lipid synthesis on IDH1 mutant AML in vivo, we engrafted primary IDH1 mutant AML and tested growth with lipid-free compared to normal diet. At 12 weeks, IDH1 mutant AML showed reduced growth in the bone marrow of mice on lipid-free diet (SU389 11% vs 40%, n=10 mice, P=0.03 and SU372 21% vs 34%, n=10, P=0.02 Mann-Whitney U). IDH1 mutant AML was susceptible to ACACA inhibition with shRNA, CRISPR targeting, or selective nanomolar inhibitors. Knockdown of ACACA with independent shRNAs caused a defect in cell growth in the presence of IDH1 R132H, but not in its absence or with scrambled shRNA (p=0.009, shRNA #1 vs. scrambled; p=0.01, shRNA #2 vs. scrambled) in vitro and in xenografts. Primary IDH1 R132 mutated AML blasts were selectively sensitive to ACACA inhibitor treatment compared to IDH1 wildtype normal karyotype blasts (IC50 0.6 uM vs 6 uM, p=0.009). Notably, IDH1-mutant AML blasts pre-treated with 10mM AG-120 remained susceptible to ACACA inhibition, identifying a 2-HG independent vulnerability. Similar findings were observed in a solid tumor IDH1 mutant sarcoma model in vivo. Conclusion : These results support our hypothesis that IDH1 mutant AML exhibits a defect in de novo fatty acid synthesis conferring preferential susceptibility to ACACA inhibition, and suggests that pharmacologic inhibitors of ACACA may complement IDH1 mutation-specific inhibitors in the clinic. Disclosures No relevant conflicts of interest to declare.

Boolean Implication Mining for Synthetic Lethal Interactions in AML Identifies Acetyl-CoA Carboxylase As a Synthetic Lethal Partner of the IDH1 mutation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1404-1404
Author(s):  
Subarna Sinha ◽  
Daniel Thomas ◽  
Steven M. Chan ◽  
Yang Gao ◽  
Rolf Jansen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Oxidative Phosphorylation ◽  
De Novo ◽  
Synthetic Lethality ◽  
Idh1 Mutation ◽  
Acetyl Coa Carboxylase ◽  
Synthetic Lethal ◽  
Recurrent Mutations ◽  
Pan Cancer ◽  
Boolean Implication

Abstract Introduction: Somatic mutations in cancer can directly or indirectly perturb signalling and metabolic pathways that can render a cancer cell susceptible to synthetic lethality. We have developed a novel computational method to accelerate identification of synthetic lethal partners for recurrent mutations in acute myeloid leukemia. Our method is based on the hypothesis that, across multiple cancers, synthetic lethal partners of a mutation will be amplified more frequently or deleted less frequently, with concordant changes in expression, in primary tumor samples harboring the mutation of interest.It uses Boolean implication (if-then rules) mining (Sinha et al, Blood 2015) to efficiently identify candidate synthetic lethal partners of a given mutation. The method is distinct from existing work in that it is not reliant on data collected from cell-lines, which are not biologically equivalent to primary tissue and do not always share the composition of mutations found in vivo, but instead utilizes large pan-cancer primary patient datasets. Pan-cancer analysis discovers robust relationships that are more likely to be independent of cancer subtypes, as well as increases statistical power. Methods: We utilized TCGA data of 12 non-AML cancer data-sets (TCGA Research Network et al, Nat. Gen. 2013) for which recurrent AML mutations were present with a frequency of at least 2.5%. These mutations include Cohesin, IDH1, WT1, KRAS, and RUNX1. Boolean implications (FDR < 0.05) were used to identify genes that have more copies in the presence of a mutation as determined by (i) preferred amplification in the presence of the mutation - if gene B is amplified, then mutation A is present, (ii) deletion only in the absence of the mutation - if mutation A is present, then gene B is not deleted. Next, we remove genes that are passengers in large chromosomal alterations using gene expression filtering. Finally, the resulting gene set is filtered by differential gene expression in AML to yield the set of candidate synthetic lethal (SL) partners for a given mutation in AML. Results: To validate our novel method, we compared our putative SL partners to an independent shRNA library screen (DECIPHER) performed in our laboratory for the IDH1 R132 mutation (mut) expressed in THP-1 cells using a doxycycline-inducible promoter (Chan et al, Nat. Med. 2015). We found 6 out of 29 predicted genes showed synthetic lethality when knocked down in the presence of the mutation (Fisher's exact test, p=0.002) indicating our method could find experimentally confirmed interactions. Interestingly, our method predicted Bcl-w to be a SL partner of IDH1 mut, consistent with the SL interaction we previously described between Bcl-2 family members and IDH1 mut in primary AML. Importantly, we found that acetyl-CoA carboxylase alpha (ACACA), the rate-limiting enzyme that controls lipid biosynthesis, was predicted to be a strong SL partner for IDH1 mut. Selective inhibition of ACACA with independently validated shRNA or the small molecule inhibitors, 5-(tetradecyloxy)-2-furoic acid (TOFA) and Soraphen A, prevented cell proliferation in the presence of IDH1 mut but not with IDH1 wildtype. (R)-2-hydroxyglutarate inhibited oxidative phosphorylation and sensitised cells to ACACA inhibitors suggesting the interaction was mediated through the oncometabolite. Gene expression profiling of IDH1 mut cells indicated upregulation of lipid biogenesis pathways (PHOSPHOLIPID METABOLISM, p=0.001). Furthermore, gene expression of ACACA is higher in primary IDH1 mut samples compared to IDH1 wildtype (p=0.008, fold change = 1.2), and cultured primary IDH1mut blasts show selective sensitisation to ACACA inhibition in vitro (n=5/6 IDH1mut/IDH1 wt, p=0.04). Conclusion: We have developed a computational tool that can predict SL interactions for recurrent mutations in AML, with applicability to other cancers. Our method identified de novo lipogenesis as a critical metabolic pathway linked to a specific mutation and suggests therapeutic inhibition of ACACA with small molecules may be beneficial in IDH1 mut AML. This is consistent with recent understanding of the Warburg effect, which postulates that certain oncogenic mutations may indirectly stimulate macromolecule biosynthesis pathways to promote unrestrained cell growth. Our results indicate that a function of the IDH1 mutation is to inhibit oxidative phosphorylation and stimulate de-novo lipid synthesis. Disclosures Majeti: Forty Seven, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals IDH1 Mutation in Gliomas in Mosul City - Iraq

2015 ◽  
Vol 3 (2) ◽  
pp. 250-255 ◽  
Author(s):  
Mohammed Sami Saeed
Keyword(s):  
Case Series ◽  
Idh1 Mutation ◽  
Teaching Hospitals ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Secondary Glioblastoma ◽  
Idh1 R132h ◽  
Case Series Study ◽  
Idh1 Mutations ◽  
Prospective Case Series

BACKGROUND: IDH1 (isocitrate dehydrogenase 1) mutation might be encounter in the low grade glioma and directs the progression of the tumor to a higher grade.OBJECTIVE: To assess the frequency of IDH1 mutations in gliomas and to correlate the IDH1 positivity with the type and grade of tumors, the age and sex of the patients.MATERIAL AND METHODS: A retro– and prospective case series study. One hundred and nine cases of intracranial gliomas were collected between 2008 and 2014 from Mosul Private Laboratories and Al-Jamboree Teaching Hospitals in Mosul. IDH1 mutations were assessed immunohistochemically using anti-IDH1 R132H mouse monoclonal antibody.RESULTS: IDH1 mutation was perceived in 34.86% of gliomas. In adult gliomas, the secondary glioblastoma and the low-grade astrocytoma had the greatest values of IDH1 positivity (88.88% and 62.5% respectively), followed by oligoastrocytoma/oligodendroglioma (50.0%), and anaplastic astrocytoma (47.36%). The primary glioblastomsa showed 17.64% IDH1 positivity. Males and females expressed the IDH1 equally. While, there was no role of IDH1 in pediatric gliomas.CONCLUSION: IDH1 mutation is commonly present in adult gliomas particularly in low-grade gliomas, and secondary glioblastoma, with equal sex distribution, but it has no role in pediatric gliomas.

scholarly journals Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

2020 ◽  
Author(s):  
Padma Kadiyala ◽  
Stephen V. Carney ◽  
Jessica C. Gauss ◽  
Maria B. Garcia-Fabiani ◽  
Felipe J. Núñez ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Immunological Memory ◽  
Immune Checkpoint Blockade ◽  
Metabolic Reprogramming ◽  
Lower Grade ◽  
Combination Strategy ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh1 R132h ◽  
Mutant Idh1 ◽  
Promoter Mutations

AbstractMutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas’ subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8+T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.Brief SummaryInhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity.

scholarly journals Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2–β-Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

2018 ◽  
Vol 38 (9) ◽  
Author(s):  
Pruthvi Gowda ◽  
Shruti Patrick ◽  
Ankita Singh ◽  
Touseef Sheikh ◽  
Ellora Sen
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Chromatin Immunoprecipitation ◽  
Immune Surveillance ◽  
Ectopic Expression ◽  
The Cancer Genome Atlas ◽  
Data Sets ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh1 R132h ◽  
Cancer Genome Atlas ◽  
Mutant Idh1

ABSTRACT A gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) affects immune surveillance in gliomas. As elevated CD47 levels are associated with immune evasion in cancers, its status in gliomas harboring mutant IDH1 (IDH1-MT cells) was investigated. Decreased CD47 expression in IDH1-R132H-overexpressing cells was accompanied by diminished nuclear β-catenin, pyruvate kinase isoform M2 (PKM2), and TCF4 levels compared to those in cells harboring wild-type IDH1 (IDH1-WT cells). The inhibition of β-catenin in IDH1-WT cells abrogated CD47 expression, β-catenin–TCF4 interaction, and the transactivational activity of β-catenin/TCF4. The reverse effect was observed in IDH1-MT cells upon the pharmacological elevation of nuclear β-catenin levels. Genetic and pharmacological manipulation of nuclear PKM2 levels in IDH1-WT and IDH1-MT cells suggested that PKM2 is a positive regulator of the β-catenin–TCF4 interaction. The Cancer Genome Atlas (TCGA) data sets indicated diminished CD47, PKM2, and β-catenin levels in IDH1-MT gliomas compared to IDH1-WT gliomas. Also, elevated BRG1 levels with mutations in the ATP-dependent chromatin-remodeling site were observed in IDH1-MT glioma. The ectopic expression of ATPase-deficient BRG1 diminished CD47 expression as well as TCF4 occupancy on its promoter. Sequential chromatin immunoprecipitation (ChIP–re-ChIP) revealed the recruitment of the PKM2–β-catenin–BRG1–TCF4 complex to the TCF4 site on the CD47 promoter. This occupancy translated into CD47 transcription, as a diminished recruitment of this complex was observed in glioma cells bearing IDH1-R132H. In addition to its involvement in CD47 transcriptional regulation, PKM2–β-catenin–BRG1 cross talk affected the phagocytosis of IDH1-MT cells by microglia.

TROP-2, 5hmC, and IDH1 Expression in Anaplastic Thyroid Carcinoma

2020 ◽  
pp. 106689692097859
Author(s):  
Jae Yeon Seok ◽  
Kristine Astvatsaturyan ◽  
Mariza De Peralta-Venturina ◽  
Jinping Lai ◽  
Xuemo Fan
Keyword(s):  
Thyroid Carcinoma ◽  
De Novo ◽  
Anaplastic Thyroid Carcinoma ◽  
Antibody Drug Conjugate ◽  
Isocitrate Dehydrogenase 1 ◽  
Entire Cohort ◽  
Drug Conjugate ◽  
Idh1 R132h ◽  
Novel Target ◽  
Antibody Drug

Background Anaplastic thyroid carcinoma (ATC), a highly aggressive malignancy, has no effective treatment to date. Trophoblast cell-surface antigen 2 (TROP-2), a transmembrane glycoprotein, has been suggested to be a promising novel target for sacituzumab govitecan, an antibody-drug conjugate. 5-Hydroxymethylcytosine (5hmC) has a role in tumor suppression and promoting modification. Additionally, isocitrate dehydrogenase 1 (IDH1) mutations are strongly associated with increased overall survival in gliomas and worse prognosis in leukemias. This study attempts to evaluate the immunoexpression of TROP-2, 5hmC, and IDH1 in ATCs and to determine their potential impact in targeted therapy. Methods Twenty-four ATCs were retrieved, with 9 cases that occurred de novo and 15 cases derived from either papillary thyroid carcinoma (PTC) or follicular thyroid carcinoma (FTC). Sections were immunostained with TROP-2, 5hmC, and IDH1 antibodies, and evaluated using the QuPath program. The t tests were performed using SPSS software. Results TROP-2 was detected in 12 ATCs with 9 cases demonstrating a high expression and in all PTC components, and absent in all FTC components of secondary ATCs. 5hmC expression was moderately reduced in PTC and FTC components and markedly reduced in ATC. The entire cohort showed a total absence of IDH1. Conclusions Increased TROP-2 immunoexpression in some ATCs supports that these patients may potentially benefit from an antibody-drug conjugate therapy targeting TROP-2. Markedly reduced 5hmC expression suggests that 5hmC may be used as potential therapeutic targets for ATC. The total lack of IDH1 R132H mutation by immunostain indicates that it has no prognostic and therapeutic value in ATC.

scholarly journals FSMP-07. CYSTATHIONINE-Γ-LYASE DRIVES ANTIOXIDANT DEFENSE IN CYSTEINE-RESTRICTED IDH1 MUTANT ASTROCYTOMAS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i17-i17
Author(s):  
Andrés Cano-Galiano ◽  
Anais Oudin ◽  
Fred Fack ◽  
Maria-Francesca Allega ◽  
David Sumpton ◽  
...  
Keyword(s):  
Antioxidant Defense ◽  
De Novo ◽  
Idh1 Mutation ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Astrocytic Gliomas ◽  
The Impact ◽  
Reducing Potential

Abstract Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzymes are crucial for the generation of reducing potential, yet the impact of the mutation on the cellular antioxidant system is not understood. Here, we investigate how glutathione (GSH) levels are maintained in IDH1 mutant gliomas, despite an altered NADPH/NADP balance. We find that IDH1 mutant astrocytomas specifically upregulate cystathionine γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis. Genetic and chemical interference with CSE in patient-derived glioma cells carrying the endogenous IDH1 mutation, sensitized tumor cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with reduced GSH synthesis as shown by in vitro and in vivo serine tracing and led to delayed tumor growth in mice. Thus we show that IDH1 mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis to maintain the antioxidant defense, which uncovers a novel metabolic vulnerability in this dismal disease.

scholarly journals Friend or foe—IDH1 mutations in glioma 10 years on

2019 ◽  
Vol 40 (11) ◽  
pp. 1299-1307 ◽  
Author(s):  
L Eric Huang
Keyword(s):  
Large Body ◽  
Point Mutations ◽  
Idh1 Mutation ◽  
Metabolic Reprogramming ◽  
Model Systems ◽  
Isocitrate Dehydrogenase 1 ◽  
Recurrent Point ◽  
Scientific Papers ◽  
Mutant Idh1 ◽  
Experimental Findings

Abstract The identification of recurrent point mutations in the isocitrate dehydrogenase 1 (IDH1) gene, albeit in only a small percentage of glioblastomas a decade ago, has transformed our understanding of glioma biology, genomics and metabolism. More than 1000 scientific papers have been published since, propelling bench-to-bedside investigations that have led to drug development and clinical trials. The rapid biomedical advancement has been driven primarily by the realization of a neomorphic activity of IDH1 mutation that produces high levels of (d)-2-hydroxyglutarate, a metabolite believed to promote glioma initiation and progression through epigenetic and metabolic reprogramming. Thus, novel inhibitors of mutant IDH1 have been developed for therapeutic targeting. However, numerous clinical and experimental findings are at odds with this simple concept. By taking into consideration a large body of findings in the literature, this article analyzes how different approaches have led to opposing conclusions and proffers a counterintuitive hypothesis that IDH1 mutation is intrinsically tumor suppressive in glioma but functionally undermined by the glutamate-rich cerebral environment, inactivation of tumor-suppressor genes and IDH1 copy-number alterations. This theory also provides an explanation for some of the most perplexing observations, including the scarcity of proper model systems and the prevalence of IDH1 mutation in glioma.

scholarly journals Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 889 ◽  
Author(s):  
Jacqueline Kessler ◽  
Tim Hohmann ◽  
Antje Güttler ◽  
Marina Petrenko ◽  
Christian Ostheimer ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Isocitrate Dehydrogenase ◽  
Idh1 Mutation ◽  
Cell Stiffness ◽  
Diffuse Glioma ◽  
Isocitrate Dehydrogenase 1 ◽  
Aggressive Phenotype ◽  
Γh2ax Foci ◽  
Mutant Idh1

The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments.

Low Prevalence of IDH1 gene Mutation In Childhood AML In Italy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1678-1678
Author(s):  
Martina Pigazzi ◽  
Giulia Ferrari ◽  
Riccardo Masetti ◽  
Brunangelo Falini ◽  
Francesco Martinolli ◽  
...  
Keyword(s):  
Gene Mutation ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Idh1 Mutation ◽  
Isocitrate Dehydrogenase 1 ◽  
Childhood Aml ◽  
Idh1 Mutations ◽  
Low Prevalence

Abstract Abstract 1678 Introduction: The IDH1 gene encodes for NADP+-dependent isocitrate dehydrogenase 1 enzyme, which catalyzes the oxydative decarboxylation of isocitrate to α-ketoglutarate. Acquired somatic mutations of the R132 residue of IDH1 have been detected in adults with de novo AML, while so far no IDH1 mutations were detected in a series of 257 children in USA. The role of IDH1 mutations in the pathogenesis of AML is still unclear. Material and Methods: From 01/12/2002 to 31/12/2007, 205 childhood AML patients were enrolled into the multicentric AIEOP-LAM 2001/02 protocol. Among them, we analyzed the prevalence of IDH1 mutations in 165 patients for whom material was available. IDH1 gene mutations have been analyzed by PCR amplification and sequencing of the exon 4. The clinical and biological features of the analyzed and not analyzed population were not statistically different. Results: In this series of childhood AML cases, 4 out of 165 cases (2.4%) were positive for IDH1 mutations. All patients were male, the age at diagnosis ranged from 3 to 14 years, while the WBC count at diagnosis ranged from 8750 to 233970 WBC/ml. Three of them had FAB M1 and one M2; none of them had localization in the central nervous system, while one had lymph nodes involvement. Two of the 4 children with the IDH1 mutation had a normal karyotype while two carried different clonal translocation. One patient carried the FLT3-ITD mutation at diagnosis, whereas no other known associated mutations were found. Based on cytogenetics, all of them were classified within the high risk group. Complete remission was achieved in all cases, and all but one received BMT. Two patients had a medullary relapse and all are alive, after 20, 26, 33 and 33 months from BMT. All patients carried the R132H IDH1 mutation. The mutation was specific of the leukemia cells, being absent in the remission phase of all patients. Interestingly, the R132H mutation was detected at the relapse stage of one patient, but not at the relapse of the second patient, suggesting that IDH1 mutations could represent a secondary lesion in the pathogenesis of leukemia. Because 2/4 IDH1 mutated cases in the sequential screening had a normal karyotype, we extended the mutational screening to all Italian childhood cases diagnosed as AML with normal karyotype from 13/10/2000 to 15/04/2010. Out of the additional 97 cases with normal karyotype, only 1 carried a IDH1 mutation (R132H). Conclusions: In summary, we showed that IDH1 gene mutation can be detected also in pediatric AML, with an estimate prevalence of 2.4% (4/165) in the Italian series. The low prevalence does not allow any prediction on the outcome, although all patients are alive at different time after BMT, even in the presence of FLT3-ITD mutation (one patient). The clinical and biological characteristics of the mutated patients seemed not to be different from the overall childhood AML population, and similar to the adult IDH1 mutated cases. The R132 mutation is the only pediatric mutation detected so far. The extended series to a total number of 186 childhood AML with normal karyotype identified 3/186 mutations (1.6%) in this specific subgroup. Therefore, it does not seem that IDH1 mutation is more prevalent in normal karyotype. In addition, even considering that the IDH1 mutation could not be present at the relapse (like it happens for FLT3 mutations), it is questionable the role of these abnormalities, and whether those mutations in ‘normal cytogenetic’ subgroup could be sufficient for the clinical disease emergence, or further events must be discovered in the complex and multistep pathogenesis of leukemia. Disclosures: No relevant conflicts of interest to declare.

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