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 of 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. A 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, allowing 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 two validation cohorts. 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.

High Expression of DC-STAMP Gene Predicts Adverse Outcomes in AML

“…Finally, the GSEA was used to investigate the enrichment pathway of DC-STAMP expression, and a total of 28 significant pathways were enriched ( Table 2 ). Interestingly, some pathways, such as IL6-JAK-STAT3 signaling, mTORC1 signaling, TNF-α signaling via NF-κB, INF-γ response, glycolysis, and DNA repair ( Figures 4J–L ) were reported to correlate with leukemogenesis ( Steelman et al, 2008 ; Park et al, 2010 ; Binder et al, 2018 ; Molina et al, 2018 ; Gabellier et al, 2020 ; Grants et al, 2020 ).…”

DNA damage accumulation and repair defects in FLT3‐ITD acute myeloid leukemia: Implications for clonal evolution and disease progression

“…In addition, the subclassification of these patients according to the presence or absence of NPM1 mutations and/or FLT3‐ITD revealed that the expression status of DNA repair genes can also influence the clinical prognosis of these groups, being better in patients with NPM1 mutations and low expression of DNA repair genes, while worse in patients with FLT3‐ITD and high expression of DNA repair genes. 49 This may indicate that FLT3‐ITD cells with high DNA repair are better able to repair the extensive DNA damage constantly caused by ROS, conferring proliferation and survival advantages. Moreover, damage‐repair cycles coupled with defective repair in FLT3‐ITD cells could lead to the appearance of cell clones that are more resistant to treatment and more aggressive.…”

“…In patients with cytogenetically normal acute myeloid leukemia, in whom FLT3‐ITD is a common mutation, overexpression of genes from the BER, NER, Fanconi anemia (FA), MMR, and HR pathways was associated with poor clinical prognosis. In addition, the subclassification of these patients according to the presence or absence of NPM1 mutations and/or FLT3‐ITD revealed that the expression status of DNA repair genes can also influence the clinical prognosis of these groups, being better in patients with NPM1 mutations and low expression of DNA repair genes, while worse in patients with FLT3‐ITD and high expression of DNA repair genes 49 . This may indicate that FLT3‐ITD cells with high DNA repair are better able to repair the extensive DNA damage constantly caused by ROS, conferring proliferation and survival advantages.…”