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Project description:Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients. However, only 30-40% of the patients respond to IDH inhibitors (IDHi). We aimed to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. We characterized the transcriptional and epigenetic landscape with the IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts, and discovered a perturbed transcriptional regulatory network involving myeloid transcription factors that were partly restored after AG-221 treatment. In addition, hypermethylation of the HLA cluster caused a down-regulation of HLA class I genes, triggering an enhanced natural killer (NK) cell activation and an increased susceptibility to NK cell-mediated responses. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders still harbored hypermethylation in HLA class I genes. In conclusion, this study provides new insights suggesting that IDH mutated AML is particularly sensitive to NK cell-based personalized immunotherapy.
| S-EPMC10457197 | biostudies-literature
Project description:IDH mutations are found in 20% of acute myeloid leukemia (AML) patients. IDH inhibitors (IDHi) have emerged as a novel treatment option. However, only 30-40% of patients respond to single drug treatment and there is an unmet need for improvement as well as identifying alternative treatment options. The overall aim of this study was therefore to gain deeper insights into the molecular signatures of IDH mutations, the effects of IDHi as well as to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. Here, we have characterized the transcriptional and epigenetic landscape before and after treatment with IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts. We discovered decreased DNA hydroxymethylation in IDH2 mutated AML cells, particular in enhancers and a perturbed transcriptional regulatory network involving myeloid transcription factors. In addition, hypermethylation of the HLA I cluster caused a dramatic down-regulation of HLA genes, triggering an enhanced natural killer (NK) cell activation, and displayed an increased susceptibility to NK cell mediated killing. These responses were reverted when the AML cells were pre-exposed to IFN-gamma, resulting in up-regulation of cell surface HLA class I. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders continued to harbor hypermethylation in HLA class I genes, suggesting maintained susceptibility to NK cells. In conclusion, this study provides new insights into the perturbed epigenetic and transcriptional regulation in IDH mutated AML and shed light on a potential strategy for personalized medicine in AML. Methylation/hydroxymethylation profiling by array
2023-07-09 | GSE207829 | GEO
Project description:IDH mutations are found in 20% of acute myeloid leukemia (AML) patients. IDH inhibitors (IDHi) have emerged as a novel treatment option. However, only 30-40% of patients respond to single drug treatment and there is an unmet need for improvement as well as identifying alternative treatment options. The overall aim of this study was therefore to gain deeper insights into the molecular signatures of IDH mutations, the effects of IDHi as well as to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. Here, we have characterized the transcriptional and epigenetic landscape before and after treatment with IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts. We discovered decreased DNA hydroxymethylation in IDH2 mutated AML cells, particular in enhancers and a perturbed transcriptional regulatory network involving myeloid transcription factors. In addition, hypermethylation of the HLA I cluster caused a dramatic down-regulation of HLA genes, triggering an enhanced natural killer (NK) cell activation, and displayed an increased susceptibility to NK cell mediated killing. These responses were reverted when the AML cells were pre-exposed to IFN-gamma, resulting in up-regulation of cell surface HLA class I. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders continued to harbor hypermethylation in HLA class I genes, suggesting maintained susceptibility to NK cells. In conclusion, this study provides new insights into the perturbed epigenetic and transcriptional regulation in IDH mutated AML and shed light on a potential strategy for personalized medicine in AML.
2023-07-09 | GSE207830 | GEO
Project description:Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells
| PRJNA857302 | ENA
Project description:Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [methylation]
| PRJNA857305 | ENA
Project description:Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells [TT-Seq]
| PRJNA857306 | ENA
Project description:The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18-92). There were 59 IDH1-R132, 83 IDH2-R140, and 23 IDH2-R172 mutations. Clinicopathologic characteristics associated with IDH-mutations included older age, less frequent therapy-related status, and increased incidence of intermediate-risk cytogenetics, FLT3-ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage-1 (S1), 42%; and Salvage-2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH-mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies.
| S-EPMC4612499 | biostudies-other
Project description:Mutations in the isocitrate dehydrogenase (IDH1 or IDH2) genes are common in enchondromas and chondrosarcomas, and lead to elevated levels of the oncometabolite D-2-hydroxyglutarate causing widespread changes in the epigenetic landscape of these tumors. With the use of a DNA methylation array, we explored whether the methylome is altered upon progression from IDH mutant enchondroma towards high-grade chondrosarcoma. High-grade tumors show an overall increase in the number of highly methylated genes, indicating that remodeling of the methylome is associated with tumor progression. Therefore, an epigenetics compound screen was performed in five chondrosarcoma cell lines to therapeutically explore these underlying epigenetic vulnerabilities. Chondrosarcomas demonstrated high sensitivity to histone deacetylase (HDAC) inhibition in both 2D and 3D in vitro models, independent of the IDH mutation status or the chondrosarcoma subtype. siRNA knockdown and RNA expression data showed that chondrosarcomas rely on the expression of multiple HDACs, especially class I subtypes. Furthermore, class I HDAC inhibition sensitized chondrosarcoma to glutaminolysis and Bcl-2 family member inhibitors, suggesting that HDACs define the metabolic state and apoptotic threshold in chondrosarcoma. Taken together, HDAC inhibition may represent a promising targeted therapeutic strategy for chondrosarcoma patients, either as monotherapy or as part of combination treatment regimens.
| S-EPMC7760027 | biostudies-literature
Project description:Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged between <1 month and 88 years treated on Children's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): pediatric (0-17, 1744), adolescent/young adult (18-39, 444), intermediate-age (40-59, 640), older (≥60, 309). IDH mutations (IDHmut) were identified in 9.2% of the total cohort (n = 288; IDH1 [n = 123, 42.7%]; IDH2 [n = 165, 57.3%]) and were strongly correlated with increased age: 3.4% pediatric vs 21% older, P < .001. Outcomes were similar in IDHmut and IDH-wildtype (IDHWT) AML (event-free survival [EFS]: 35.6% vs 40.0%, P = .368; overall survival [OS]: 50.3% vs 55.4%, P = .196). IDH mutations frequently occurred with NPM1 (47.2%), DNMT3A (29.3%), and FLT3-internal tandem duplication (ITD) (22.4%) mutations. Patients with IDHmut AML with NPM1 mutation (IDHmut/NPM1mut) had significantly improved survival compared with the poor outcomes experienced by patients without (IDHmut/NPM1WT) (EFS: 55.1% vs 17.0%, P < .001; OS: 66.5% vs 35.2%, P < .001). DNTM3A or FLT3-ITD mutations in otherwise favorable IDHmut/NPM1mut AML led to inferior outcomes. Age group analysis demonstrated that IDH mutations did not abrogate the favorable prognostic impact of NPM1mut in patients aged <60 years; older patients had poor outcomes regardless of NPM1 status. These trials were registered at www.clinicaltrials.gov as #NCT00070174, #NCT00372593, #NCT01371981, #NCT00049517, and #NCT00085709.
| S-EPMC10562769 | biostudies-literature
Project description:Inhibition of the H3K79 histone methyltransferase DOT1L has exhibited encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has been reported to have preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we observed both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2-mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 chromatin immunoprecipitation sequencing patterns over ribosomal genes were similar to those of the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process-protein synthesis-that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity.
| S-EPMC8362846 | biostudies-literature