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Gene expression profiling of CEBPA double-, single-mutant and CEBPA wild type AML

ABSTRACT: A previously predictive CEBPA double mutant (CEBPAdm) signature was hampered by the recently reported CEBPA silenced AML cases that carry a similar gene expression profile (GEP). Two independent AML cohorts were used to train and evaluate the predictive value of the CEBPAdm signature in terms of sensitivity and specificity. A predictive signature was created, containing 25-probe sets by using a logistic regression model with Lasso regularization, which selects discriminative probe sets between the classes, CEBPAdm and all other AML cases, CEBPA wild type (CEBPAwt) and CEBPA single mutant (CEBPAsm). Subsequently, a classifier was trained on the entire HOVON-SAKK cohort based on a two-class approach; CEBPAdm versus all other cases (CEBPAwt and CEBPAsm). This trained classifier subsequently classified 16 candidate CEBPAdm cases in the AMLSG-cohort out of 154 AML cases. This approach showed perfect sensitivity and specificity (both 100%). In addition, we have performed a classification between CEBPAdm ,CEBPAsm, and CEBPAwt to infer if we were able to accurately classify CEBPAsm cases. We observed that all CEBPAsm cases were classified as CEBPAwt, thus CEBPAsm cases do not have a consistent gene expression pattern and are different from the CEBPAdm group.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22845 | GEO | 2011/08/04

SECONDARY ACCESSION(S): PRJNA128053

REPOSITORIES: GEO

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Gene expression profiling of CEBPA double-, single-mutant and CEBPA wild type AML

Project description:A previously predictive CEBPA double mutant (CEBPAdm) signature was hampered by the recently reported CEBPA silenced AML cases that carry a similar gene expression profile (GEP). Two independent AML cohorts were used to train and evaluate the predictive value of the CEBPAdm signature in terms of sensitivity and specificity. A predictive signature was created, containing 25-probe sets by using a logistic regression model with Lasso regularization, which selects discriminative probe sets between the classes, CEBPAdm and all other AML cases, CEBPA wild type (CEBPAwt) and CEBPA single mutant (CEBPAsm). Subsequently, a classifier was trained on the entire HOVON-SAKK cohort based on a two-class approach; CEBPAdm versus all other cases (CEBPAwt and CEBPAsm). This trained classifier subsequently classified 16 candidate CEBPAdm cases in the AMLSG-cohort out of 154 AML cases. This approach showed perfect sensitivity and specificity (both 100%). In addition, we have performed a classification between CEBPAdm ,CEBPAsm, and CEBPAwt to infer if we were able to accurately classify CEBPAsm cases. We observed that all CEBPAsm cases were classified as CEBPAwt, thus CEBPAsm cases do not have a consistent gene expression pattern and are different from the CEBPAdm group. All samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation. Routine diagnostic algorithms, including the characterization of molecular markers are performed.

2011-08-03 | E-GEOD-22845 | biostudies-arrayexpress

Acute myeloid leukemia with CEBPA double-mutations harbors in 76.8% of cases concomitant molecular mutations with TET2 and GATA2 alterations demonstrating strong prognostic impact

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.

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by re-balancing GATA2 expression

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [WGBS]

Project description:The myeloid transcription factor CEBPA is recurrently biallelically mutated (i.e., double mutated; CEBPADM) in acute myeloid leukemia (AML) with a combination of hypermorphic N-terminal mutations (CEBPANT), promoting expression of the leukemia-associated p30 isoform, and amorphic C-terminal mutations. CEBPADM AML features recurrent co-occurring mutations including GATA2 lesions, however insights into mechanisms governing this co-mutational spectrum are incomplete. By combining transcriptomic and epigenomic analyses of CEBPA-TET2 co-mutated patients with models thereof, we identify GATA2 as a conserved target of the CEBPA-TET2 mutational axis, providing a rationale for the mutational spectra in CEBPADM AML. Mechanistically, we suggest that elevated CEBPA levels, driven by CEBPANT, mediate recruitment of TET2 to the Gata2 distal hematopoietic enhancer thereby increasing Gata2 expression. Conversely, CEBPADM AML gains a competitive advantage through TET2 loss, by decreasing Gata2 promoter demethylation thereby rebalancing GATA2 levels. Of clinical relevance, demethylating treatment of Cebpa-Tet2 co-mutated AML restores Gata2 levels and prolongs disease latency.

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TET2 lesions enhance the aggressiveness of CEBPA-mutant AML by rebalancing GATA2 expression [RNA-Seq]

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Acute myeloid leukemia with CEBPA double-mutations harbors in 76.8% of cases concomitant molecular mutations with TET2 and GATA2 alterations demonstrating strong prognostic impact

2013-04-20 | GSE42064 | GEO

Transcription profiling of human newly diagnosed AML CEBPA double and single mutant and CEBPA wild type AML.

Project description:Mutations in CCAAT/enhancer binding protein alpha (CEBPA) are seen in 5-14% of acute myeloid leukemia (AML) and have been associated with a favorable clinical outcome. Most AMLs with CEBPA mutations simultaneously carry two mutations (CEBPAdouble-mut), usually biallelic, while single heterozygous mutations (CEBPAsingle-mut) are less frequently seen. Using denaturing high performance liquid chromatography and nucleotide sequencing we identified among a cohort of 598 newly diagnosed AMLs a subset of 41 CEBPA mutant cases, i.e. 28 CEBPAdouble-mut and 13 CEBPAsingle-mut cases. CEBPAdouble-mut associated with a unique gene expression profile as well as favorable overall and event-free survival, retained in multivariable analysis that included cytogenetic risk, FLT3-ITD and NPM1 mutation, white blood cell count and age. In contrast, CEBPAsingle-mut AMLs did not express a discriminating signature and could not be distinguished from wild type cases as regards clinical outcome. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Experiment Overall Design: Gene expression profiling of 524 cases of de novo AML. Comparisons of cases with double and single CEBPA mutations versus those with wild type CEBPA.

2009-01-23 | E-GEOD-14468 | biostudies-arrayexpress

Genome-wide DNA methylation in CEBPA mutant and CEBPA silenced AML

Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: DNA methylation profiling Direct comparison of DNA methylation in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression. Two control groups are included: 8 CD34+ bone marrow samples from healthy donors and 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.

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Gene expression profiling of CEBPA double and single mutant and CEBPA wild type AML.

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Transcription profiling of human CEBPA mutant and CEBPA silenced AML and in T-ALL

Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Experiment Overall Design: Direct comparison of gene expression in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression, and with 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.

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