Genetics and transcriptomics of human acute erythroid leukemia
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PROVIDER: EGAS00001004203 | EGA |
REPOSITORIES: EGA
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Project description:The goal of this study is to define the global gene expression profile of primary leukemic blasts from patients with different forms of myeloid leukemia and different FAB subtypes. Here we report the global gene expression profile of 2 patients with AML FAB M5, 2 patients with AML FAB M7, 3 patients with Down syndrome AML FAB M7 and 3 patients with Down syndrome transient leukemia.
2009-12-29 | GSE19681 | GEO
Project description:Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH. Functional studies have shown these mutations contribute to transformation, although how these mutations impact the response to epigenetic therapies is not fully delineated. Here we show AMLs with TET2/IDH2 mutations combined with FLT3ITD mutations are specifically sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine/AG-221 therapies induced a reduction in leukemic blasts and in stem/progenitor expansion, with attenuation of aberrant DNA hypermethylation. These therapeutic benefits were achieved through restoration of differentiation, such that normalized hematopoiesis was derived from mutant cells. Consistent with these data, at the time of clinical response to 5-Azacytidine or AG-221, most patients had mutant-derived hematopoiesis. By contrast, combined AG-221/5-Azacytidine plus FLT3 inhibition reduced disease burden and reversed epigenetic dysfunction. Our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.
2017-02-25 | GSE78691 | GEO
Project description:Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH. Functional studies have shown these mutations contribute to transformation, although how these mutations impact the response to epigenetic therapies is not fully delineated. Here we show AMLs with TET2/IDH2 mutations combined with FLT3ITD mutations are specifically sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine/AG-221 therapies induced a reduction in leukemic blasts and in stem/progenitor expansion, with attenuation of aberrant DNA hypermethylation. These therapeutic benefits were achieved through restoration of differentiation, such that normalized hematopoiesis was derived from mutant cells. Consistent with these data, at the time of clinical response to 5-Azacytidine or AG-221, most patients had mutant-derived hematopoiesis. By contrast, combined AG-221/5-Azacytidine plus FLT3 inhibition reduced disease burden and reversed epigenetic dysfunction. Our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.
2017-02-25 | GSE78690 | GEO
Project description:Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation in mutant leukemic blasts and may provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, most responders eventually relapse. To understand the molecular underpinnings of clinical resistance, we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1/IDH2-mutant AML patients treated with IDH inhibitors (IDHi), and described the evolution of AML genome and epigenome during the therapy and its association with clinical response and relapse. Co-occurrence of mutations in RUNX1/CEBPA or RAS-RTK pathway genes were associated with poor response to IDHi. The same group of mutations were also frequently selected or acquired at relapse. In addition, acquired mutations in BCOR, reciprocal IDH gene, and TET2 were also implicated at relapse. DNA methylation changes largely mirrored plasma 2HG dynamics and had little association with clinical response to IDHi. The mapping of mutation dynamics and methylation changes in longitudinal samples revealed the interplay between AML genome and epigenome with IDHi therapy. While the alteration in RAS-RTK signaling genes and RUNX1/CEBPA were the key molecular pathways involved in clinical resistance to IDHi, diverse molecular pathways were involved in IDHi resistance. The data highlights the role of clonal heterogeneity in therapeutic resistance in AML and implicates opportunities for novel combination strategies.
2021-03-11 | GSE153348 | GEO
Project description:Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation in mutant leukemic blasts and may provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, most responders eventually relapse. To understand the molecular underpinnings of clinical resistance, we performed multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 68 IDH1/IDH2-mutant AML patients treated with IDH inhibitors (IDHi), and described the evolution of AML genome and epigenome during the therapy and its association with clinical response and relapse. Co-occurrence of mutations in RUNX1/CEBPA or RAS-RTK pathway genes were associated with poor response to IDHi. The same group of mutations were also frequently selected or acquired at relapse. In addition, acquired mutations in BCOR, reciprocal IDH gene, and TET2 were also implicated at relapse. DNA methylation changes largely mirrored plasma 2HG dynamics and had little association with clinical response to IDHi. The mapping of mutation dynamics and methylation changes in longitudinal samples revealed the interplay between AML genome and epigenome with IDHi therapy. While the alteration in RAS-RTK signaling genes and RUNX1/CEBPA were the key molecular pathways involved in clinical resistance to IDHi, diverse molecular pathways were involved in IDHi resistance. The data highlights the role of clonal heterogeneity in therapeutic resistance in AML and implicates opportunities for novel combination strategies.
2021-03-11 | GSE153347 | GEO
Project description:Mutations in isocitrate dehydrogenase 2 (IDH2) occur in many cancers including Acute Myeloid Leukemia (AML). In preclinical models mutant IDH2 causes partial hemopoietic differentiation arrest. Recently, we showed that single agent Enasidenib, a first-in-class, selective mutant IDH2 inhibitor, produces a 40% response in relapsed/refractory AML patients by promoting differentiation. Yet, the rate, extend and duration of the clinical benefits of Enasidenib vary from one patient to another. To investigate how the genetic mutational landscape, at baseline or at relapse, contributes in modulating response to Enasidenib, WES analyses on FACS-sorted blasts from baseline, best response and/or relapse samples from 16 Enasidenib-treated patients were performed. WES analyses were also performed on the CD3+ cells from the same patients, which may be used as germinal control samples.
2018-08-13 | E-MTAB-6299 | biostudies-arrayexpress
Project description:Purpose: The tet oncogene family member 2 (TET2) gene was recently identified mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional role of TET2 mutations (TET2mut) in AML. Thus, we explored frequency, gene expression pattern, and clinical impact of TET2mut in a large cohort of AML patients, in the context of other AML-associated aberrations. Patients and Methods: Samples from 783 younger adult AML patients were analyzed for the presence of TET2mut (coding exons 3-11), and results were correlated with data from molecular genetic analyses, gene expression profiling, and clinical outcome. Results: In total, 66 TET2mut were found in 60 (60/783; 7.6%) patients, including missense (n=37), frameshift (n=16), and nonsense (n=13) mutations, which with one exception were all heterozygous. TET2mut were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDHmut) that were almost mutually exclusive with TET2mut (p<0.001). TET2mut were characterized by only a weak gene expression pattern, which nevertheless reflected TET2mut-associated biology. TET2mut did not impact response to induction therapy and clinical outcome; combining patients exhibiting TET2mut and/or IDHmut revealed shorter overall survival (p=0.03), although this association was not independent from known risk factors. Conclusion: TET2mut were identified in 7.6% of younger adult AML patients and did not impact response to therapy and survival. Mutations were mutually exclusive with IDHmut, thereby supporting recent data on a common mechanism of action, which might obscure the impact of TET2mut if compared against all other AML cases. We performed a supervised class comparison analysis comparing 31 TET-mutated AML cases (TET2 mut) vs. 302 TET2-wildtype AML cases (TET wt) to see if a specific gene expression pattern associated with the presence of the identified TET2 mutations could be determined. No technical replicates were performed.
2011-12-31 | E-GEOD-32246 | biostudies-arrayexpress
Project description:Loss-of-function mutations of TET2 and TP53 genes are frequently co-observed in AML patients receiving intensive chemotherapy and represent independent predictors for inferior survival in patients after stem cell transplantation. Here we show that TET2 biallelic loss or haploinsufficiency is observed in >10% AML patients with TP53 mutations and associated with poor outcome. In mice, double deletions of TET2 and P53 leads to development of T-ALL, B-ALL or AML and stimulation of pre-leukemic mice via TLR2-TRAF6-A20 axis skews leukemia development toward AML. scRNA-seq of murine blasts reveals that B cell leukemia differentiation is accompanied by transcriptional changes of ll7r and Myb while AML commitment is associated with dynamic elevation of Klf4 and Flt3. Notably, mice with AML exhibit T cell exhaustion, NK dysfunction, and MDSC-like properties which are similarly observed in AML patients with TP53/TET2 co-mutations. Lastly, we demonstrated that silencing of MEK/ERK, JAK/STAT or TLR-A20 signaling pathways, that are overexpressed in TP53/TET2-mutant AML, restores normal differentiation in vitro and in vivo. Collectively, these findings provide evidence that TP53 deficiency and TET2 loss cooperate to transform hematopoietic progenitors and play a role in AML development and identify novel targets to deliver therapy for this high-risk AML group.
2023-11-13 | GSE217867 | GEO
Project description:Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes implicated in epigenetic mechanisms such as TET2 or EZH2. We have performed genome-wide methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis enrichment in a gene network centered in PLC, JNK and ERK, a recently described pathway involved in CMML was found, suggesting the potential role of epigenetics in the regulation of these pathways. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65.2%), 4 patients (16.6%) and 1 patient (4.1%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with the presence of altered karyotypes a known prognostic factor in CMML. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile. 24 samples of CMML patients, 4 healthy donor Peripheral Blood samples and 4 healthy donor Bone Marror samples
2012-02-13 | E-GEOD-31600 | biostudies-arrayexpress
Project description:Recurrent gene mutations, chromosomal translocations, acquired genomic copy number aberrations (aCNA) and copy-neutral loss-of-heterozygosity (cnLOH) underlie the genomic pathogenesis of acute myelogenous leukemia (AML). Genomic lesion types from all of these categories have been variously associated with AML patient outcome. However, the patterns of co-occurrence of such lesions are only now beginning to be defined, and we seek to further delineate the relative influence of different types of genomic alterations on clinical outcomes in AML. In this study, we performed SNP 6.0 array-based genomic profiling of aCNA/cnLOH along with sequence analysis of 13 recurrently mutated genes on purified leukemic blast DNA from 156 prospectively enrolled non-FAB-M3 AML patients across the clinical spectrum of de novo, secondary, and therapy-related AML. We identify positive and negative associations of gene mutations, specific aCNA/cnLOH or total aCNA/cnLOH counts with different AML types as well as the associations of specific mutations with overall genomic complexity or genomic stability. Further, we show that NPM1, RUNX1, ASXL1 and TP53 mutations, elevated SNP-A-based genomic complexity, and specific recurrent aCNAs predict response to induction chemotherapy. Finally, results of comprehensive multivariate analyses support a dominant role for TP53 mutations or elevated genomic complexity as predictors of short survival in AML. Integrated genomic profiling of a clinically relevant adult AML population reveals the interplay between gene mutations, recurrent aCNAs, and SNP-A-based genomic complexity and identifies among them the genomic characteristics most associated with types of response to intensive induction therapies and with shortened overall survival. This study is based on 156 patients with previously untreated AML for which paired tumor and normal samples were available. The patients were enrolled into this study at the University of Michigan Comprehensive Cancer Center. The study was approved by the University of Michigan Institutional Review Board (IRBMED #2004-1022) and written informed consent was obtained from all patients prior to enrollment. Genomic DNA was extracted from purified AML blasts and paired buccal cells. DNA thus obtained was hybridized to Affymetrix SNP 6.0 arrays.
2015-03-01 | E-GEOD-61323 | biostudies-arrayexpress