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DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets

Abstract : Cytogenetically normal acute myeloid leukemias (CN-AML) represent about 50% of total adult AML. Despite the well-known prognosis role of gene mutations such as NPM1 mutations or FLT3 internal tandem duplication (FLT3-ITD), clinical outcomes remain heterogeneous in this subset of AML. Given the role of genomic instability in leukemogenesis, expression analysis of DNA repair genes might be relevant to sharpen prognosis evaluation in CN-AML. Publicly available gene expression profile dataset from two independent cohorts of patients with CN-AML were analyzed (GSE12417). We investigated the prognostic value of 175 genes involved in DNA repair. Among these genes, 23 were associated with a prognostic value. The prognostic information provided by these genes was summed in a DNA repair score to consider connection of DNA repair pathways. DNA repair score allowed to define a group of patients (n=87; 53,7%) with poor median overall survival (OS) of 233 days (95% CI: 184-260). These results were confirmed in the validation cohort (median OS: 120 days; 95% CI: 36-303). In multivariate Cox analysis, the DNA repair score, NPM1 and FLT3-ITD mutational status remained independent prognosis factors in CN-AML. Combining these parameters allowed the identification of three risk groups with different clinical outcomes in both training and validation cohorts. Combined with NPM1 and FLT3 mutational status, our GE-based DNA repair score might be used as a biomarker to predict outcomes for patients with CN-AML. DNA repair score has the potential to identify CN-AML patients whose tumor cells are dependent on specific DNA repair pathways to design new therapeutic avenues.
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https://hal.umontpellier.fr/hal-03014671
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Soumis le : mardi 1 décembre 2020 - 16:55:00
Dernière modification le : vendredi 9 septembre 2022 - 10:22:07
Archivage à long terme le : : mardi 2 mars 2021 - 20:03:01

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cancers-881119.pdf
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Ludovic Gabellier, Caroline Bret, Guillaume Bossis, Guillaume Cartron, Jérôme Moreaux. DNA Repair Expression Profiling to Identify High-Risk Cytogenetically Normal Acute Myeloid Leukemia and Define New Therapeutic Targets. Cancers, MDPI, 2020, 12 (10), pp.2874. ⟨10.3390/cancers12102874⟩. ⟨hal-03014671⟩

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