Integrative genomic analysis identifies multiple subtypes and therapeutic targets in acute erythroid leukemia
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PROVIDER: EGAS00001002537 | EGA |
REPOSITORIES: EGA
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Project description:Acute erythroid leukemia (AEL) is a high-risk leukemia with a distinct mutational spectrum. Here, we examined the cooperativity of loss of function alterations in leukemogenesis and tested the therapeutic tractability of each model of AEL. Using CRISPR/Cas9 genome editing, we generated six pools of lentiviral vectors with different combinations of guide RNAs and transduced Cas9-eGFP-mouse mouse hematopoietic stem and progenitor cells (HSPCs) that were used in transplant assays. Induced tumors were characterized by phenotype, genomic/epigenomic analysis and tested for sensitivity to 222 therapeutic agents. Tumor genotype determined tumor phenotype with Bcor and Tp53 driving erythroid leukemogenesis. Tumors showed acquisition of additional somatic mutations during serial passaging and by transcriptomic analysis AEL models had overexpression of transcription factors required for differentiation of megakaryocyte-erythroid progenitors and recapitulated human AEL. Dnmt3a-mutated models exhibited global hypomethylation, but hypermethylation when co-occurred with Tet2 mutations. Drug response was associated with genotype. Tp53 wild-type but Dnmt3a/Tet2 double mutant cells were the most chemo-sensitive models. ViceversaTp53-mutated AEL subtypes were chemo-resistant to several conventional chemotherapeutics but highly sensitivity to PARP inhibitors, including talazoparib. Sensitivity to talazoparib was confirmed in vivo when combined with decitabine. In conclusion, combinations of recurrently mutated genes are critical determinants of leukemia phenotype, with central roles of Tp53 and Bcor mutations in driving the erythroid leukemogenesis. Using these models as preclinical tools, we have shown the potential for bromodomain and PARP inhibition as new therapeutic strategies in AEL.
2021-02-10 | GSE147343 | GEO
Project description:Acute erythroid leukemia (AEL) is a high-risk leukemia with a distinct mutational spectrum. Here, we examined the cooperativity of loss of function alterations in leukemogenesis and tested the therapeutic tractability of each model of AEL. Using CRISPR/Cas9 genome editing, we generated six pools of lentiviral vectors with different combinations of guide RNAs and transduced Cas9-eGFP-mouse mouse hematopoietic stem and progenitor cells (HSPCs) that were used in transplant assays. Induced tumors were characterized by phenotype, genomic/epigenomic analysis and tested for sensitivity to 222 therapeutic agents. Tumor genotype determined tumor phenotype with Bcor and Tp53 driving erythroid leukemogenesis. Tumors showed acquisition of additional somatic mutations during serial passaging and by transcriptomic analysis AEL models had overexpression of transcription factors required for differentiation of megakaryocyte-erythroid progenitors and recapitulated human AEL. Dnmt3a-mutated models exhibited global hypomethylation, but hypermethylation when co-occurred with Tet2 mutations. Drug response was associated with genotype. Tp53 wild-type but Dnmt3a/Tet2 double mutant cells were the most chemo-sensitive models. ViceversaTp53-mutated AEL subtypes were chemo-resistant to several conventional chemotherapeutics but highly sensitivity to PARP inhibitors, including talazoparib. Sensitivity to talazoparib was confirmed in vivo when combined with decitabine. In conclusion, combinations of recurrently mutated genes are critical determinants of leukemia phenotype, with central roles of Tp53 and Bcor mutations in driving the erythroid leukemogenesis. Using these models as preclinical tools, we have shown the potential for bromodomain and PARP inhibition as new therapeutic strategies in AEL.
2021-02-10 | GSE147265 | GEO
Project description:Background: MicroRNAs are regulators of gene expression, mainly functioning by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To further illuminate the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation, we performed an integrative analysis of microRNA and mRNA expression data sets. Design and Methods: Both microRNA and gene expression profiles were measured in a cohort of 43 adult acute myeloid leukemia patient samples (n=42 cytogenetically normal, n=1 del7q; median age 46 years [range 23-60]) of known NPM1 mutation status (n=23 mutated, n=20 wild-type) and data integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative RT-PCR, Western Blot and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays. Results: Our integrative approach of analyzing both microRNA and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA - target mRNA interactions, we could identify and validate 77 novel candidates with known or potential implication in leukemogenesis, such as IRF2-miR-20a, KIT-miR-20a and MN1-miR-15a. Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs such as miR-29a and miR-30c might contribute to the sensitivity to cytarabine, which is observed in NPM1-mutated acute myeloid leukemia. Conclusions: Overall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA - target gene interactions of potential relevance for acute myeloid leukemia treatment. MicroRNA and gene expression profiles were measured in a cohort of 43 adult (42 cytogenetically normal and 1 del7q) acute myeloid leukemia patient samples of known NPM1 mutation status (n=23 mutated, n=20 wild-type). This submission represents the mRNA expression component of the study. The miRNA expression data will be deposited as supplementary information along with the accompanying manuscript.
2011-09-11 | E-GEOD-31644 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) with CEBPA mutations is determined as provisional entity in the current WHO. A difference in clinical outcome between single- (sm) and double-mutated (dm) cases has been reported, whereupon dm cases were shown to be associated with longer overall survival (OS). The occurrence and prognostic impact of concomitant molecular mutations in addition to CEBPAdm has not been assessed until now. Here, we investigated a cohort of 95 AML CEBPAdm cases for concomitant mutations. TET2 was found to be the most frequent mutation (32/94, 34.0%), followed by GATA2 (20/95, 21.0%), WT1 (13/95, 13.7%), DNMT3A (9/94, 9.6%), ASXL1 (9/95, 9.5%), NRAS (8/95, 8.4%), KRAS (3/94, 3.2%), IDH1/2 (6/95, 6.3%), FLT3-ITD (6/95, 6.3%), FLT3-TKD (2/95, 2.1%), NPM1 (2/95, 2.1%), and RUNX1 (1/94). No mutation was detected in MLL-PTD and TP53. With respect to prognostic impact, we observed that those cases harboring additional mutations in TET2 showed significant worse survival than wild-type cases (P=0.035), whereas GATA2 mutated cases showed improved survival (P=0.032). Further, using gene expression microarray analysis we identified no clear different clustering within the CEBPAdm cases with the distinct concomitant mutated genes. In conclusion, we demonstrated that 76.8% of CEBPAdm cases harbored additional alterations in other molecular markers and that CEBPA is a suitable MRD marker to control therapy. Total cohort contains 95 cases, but expression data available for 38 cases which were analyzed on Affymetrix HG-U133 Plus 2.0 arrays: 8 CEBPAdm and GATA2 mutated cases, 12 CEBPAdm and TET2 mutated cases, 7 CEBPAdm and ASXL1 mutated cases (n=3 showed an additional TET2 mutation) and 11 CEBPAdm without mutations in GATA2, TET2, and ASXL1.
2013-04-20 | E-GEOD-42064 | 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
Project description:PURPOSE: To evaluate frequency, biological features and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n=269) microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 of 945 (5.6%) cases, predominantly in exons 3 (n=11), 4 (n=10) and 8 (n=23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46/640, 7.2%; cytogenetically normal, 34/538, 6.3%), they were less frequent in adverse-risk cytogenetics (5/109, 4.6%), and absent in core-binding-factor AML (0/77) and acute promyelocytic leukemia (0/61); RUNX1 mutations were associated with MLL-partial tandem duplications (p=0.0007) and IDH1/IDH2 mutations (p=0.03), inversely correlated with NPM1 (p<0.0001) and in trend with CEBPA (p=0.10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3) or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, p=0.047, for RUNX1-mutated and wildtype patients, respectively), as well as inferior event-free survival (EFS; p<0.0001), relapse-free survival (RFS, p=0.022), and overall survival (p=0.051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (p=0.007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (p<0.0001). CONCLUSION: AML with RUNX1 mutations exhibit distinct biological properties and are associated with resistance to therapy and inferior outcome. A total of 269 RNA samples derived from adult AML patients were provided by the German Austrian AML Study Group (AMLSG) [AMLSG trial AML HD98A (ClinicalTrials.gov Identifier: NCT00146120)]. Conventional cytogenetic banding, and FLT3, CEBPA and NPM1 mutational analysis were performed as previously described (Schlenk et al., N Engl J Med 2008). Detailed clinical, cytogenetic and molecular cytogenetic information are also provided in the supplementary information. Following enrichment, all samples contained at least 80% leukemic cells. Gene expression profiling (GEP) was performed as previously described (Bullinger et al., N Engl J Med 2004).
2010-12-31 | E-GEOD-23312 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) carrying NPM1 mutations and cytoplasmic nucleophosmin (NPMc+ AML) accounts for about one-third of adult AML and shows distinct features, including a unique gene expression profile. MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nucleotides in length that have been linked to the development of cancer. Here, we investigated the role of miRNAs in the biology of NPMc+ AML. The miRNA expression was evaluated in 85 adult de novo AML patients characterized for subcellular localization/mutation status of NPM1 and FLT3 mutations using a custom microarray platform. Data were analyzed by using univariate t test within BRB tools. We identified a strong miRNA signature that distinguishes NPMc+ mutated (n = 55) from the cytoplasmic-negative (NPM1 unmutated) cases (n = 30) and includes the up-regulation of miR-10a, miR-10b, several let-7 and miR-29 family members. Many of the down-regulated miRNAs including miR-204 and miR-128a are predicted to target several HOX genes. Indeed, we confirmed that miR-204 targets HOXA10 and MEIS1, suggesting that the HOX up-regulation observed in NPMc+ AML may be due in part by loss of HOX regulators-miRNAs. FLT3-ITD+ samples were characterized by up-regulation of miR-155. Further experiments demonstrated that the up-regulation of miR-155 was independent from FLT3 signaling. Our results identify a unique miRNA signature associated with NPMc+ AML and provide evidence that support a role for miRNAs in the regulation of HOX genes in this leukemia subtype. Moreover, we found that miR-155 was strongly but independently associated with FLT3-ITD mutations.
2008-03-14 | E-TABM-429 | biostudies-arrayexpress
Project description:Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 Black patients with AML (Alliance) and compared somatic mutation frequencies with those of 323 White patients (BeatAML). Seventy-three percent of 162 recurrent gene mutations identified in Black patients, including a novel PHIP alteration detected in 7% of patients, were found in only ≤1 White patient. Black patients with myelodysplasia-related AML were younger than White patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable outcome analyses of Black patients, NPM1 and NRAS mutations associated with inferior disease-free and IDH1/2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and White NPM1-mutated patients. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic-risk stratification changed risk-group assignment for one-third of Black patients and improved their outcome prediction.
2024-05-31 | GSE266498 | GEO
Project description:Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 Black patients with AML (Alliance) and compared somatic mutation frequencies with those of 323 White patients (BeatAML). Seventy-three percent of 162 recurrent gene mutations identified in Black patients, including a novel PHIP alteration detected in 7% of patients, were found in only ≤1 White patient. Black patients with myelodysplasia-related AML were younger than White patients suggesting intrinsic and/or extrinsic dysplasia-causing stressors. On multivariable outcome analyses of Black patients, NPM1 and NRAS mutations associated with inferior disease-free and IDH1/2 mutations with reduced overall survival. Inflammatory profiles, cell type distributions and transcriptional profiles differed between Black and White NPM1-mutated patients. Incorporation of ancestry-specific risk markers into the 2022 European LeukemiaNet genetic-risk stratification changed risk-group assignment for one-third of Black patients and improved their outcome prediction.
2024-05-01 | GSE266099 | GEO
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.
2015-03-01 | GSE61323 | GEO