RNA sequencing for AML patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE249138 | GEO | 2023/12/05
REPOSITORIES: GEO
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Project description:Multilineage dysplasia (MLD) has no impact on biological, clinico-pathological and prognostic features of AML with mutated nucleophosmin (NPM1) NPM1-mutated AML is a provisional entity in the WHO-2008 classification of myeloid neoplasms. The significance of concomitant multilineage dysplasia (MLD) in NPM1-mutated AML is unclear. Thus, in the WHO-2008 classification, NPM1-mutated AML with MLD is classified as AML with myelodysplasia(MD)-related changes. We evaluated the MLD impact in 378 NPM1-mutated AML patients. MLD was found in about 25% cases. Except for a lower WBC and FLT3-ITD incidence in MLD+ group, no significant differences were observed in age, sex, cytogenetics and FLT3-TKD between NPM1-mutated AML with and without MLD. Notably, NPM1-mutated AML with/without MLD showed overlapping immunophenotype (CD34-negativity) and GEP (CD34 downregulation and HOX genes upregulation). Moreover, OS and EFS did not differ among NPM1-mutated AML patients, independently of whether they carried or not MLD, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Lack of MLD impact on survival was confirmed by multivariate analysis that highlighted FLT3-ITD as the most significant prognostic parameter in NPM1-mutated AML. Our findings indicate that NPM1 mutations rather than MLD dictate the distinctive features of NPM1-mutated AML. Thus, irrespective of MLD, NPM1-mutated AML should be considered as one disease entity clearly distinct from AML with MD-related changes. These findings have important diagnostic and prognostic implications in AML. All bone marrow 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. 48 samples
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Project description:An increasing body of work reveals aberrant hypermethylation of genes occurring in and potentially contributing to the pathogenesis of myeloid malignancies. Several of these diseases, such as myelodysplastic syndromes (MDS), are responsive to DNA methyltransferase inhibitors. In order to determine the extent of promoter hypermethylation in such tumors we compared the distribution of DNA methylation of 14,000 promoters in MDS and secondary AML patients enrolled in a phase I trial of 5-azacytidine and the histone deacetylase inhibitor entinostat against de novo AML patients and normal CD34+ bone marrow cells. The MDS and secondary AML patients displayed more extensive aberrant DNA methylation involving thousands of genes than did the normal CD34+ bone marrow cells or de novo AML blasts. Aberrant methylation in MDS and secondary AML tended to affect particular chromosomal regions, occurred more frequently in Alu poor genes, and included prominent involvement of genes involved in the WNT and MAPK signaling pathways. DNA methylation was also measured at days 15 and 29 after the first treatment cycle. DNA methylation was reversed at day 15 in a uniform manner throughout the genome, and this effect persisted through day 29, even without continuous administration of the study drugs. Keywords: DNA methylation profiling Direct comparison of DNA methylation in bone marrow samples from patients with Myelodysplastic syndrome or secondary Acute Myeloid Leukemia (AML) at baseline and after in vivo treatment with 5-azacytidine + etinostat. A comparison to de novo normal karyotype AML was also performed. Two control groups were included: one consisting of 8 CD34+ bone marrow samples from healthy donors and a second one consisting of matched CD34+ and CD34- fractions from the bone marrows of 4 healthy donors.
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