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

Ludovic Gabellier,Caroline Bret,Jérôme Moreaux,Guillaume Bossis,Guillaume Cartron

doi:10.3390/cancers12102874

Abstract

Simple SummaryAcute myeloid leukemia (AML) is the second most frequent type of adult leukemias. Cytogenetically normal acute myeloid leukemias represent about 50% of total adult AML, exhibit no chromosomal abnormalities, and present high heterogeneity regarding the clinical outcome. Deregulation of DNA repair mechanisms is involved in the adaptation of cancer cells to replicative stress and resistance to genotoxic agents. We investigate the prognostic value of genes related to the major DNA repair pathways. The data reveals specific patterns of gene expression in CN-AML that have prognostic value. Combined with NPM1 and FLT3 mutational status, our gene expression-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 targeted therapies.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.

Highlights

Acute myeloid leukemia (AML) is the second most frequent type of adult leukemias
Considering the important role of DNA repair in drug resistance and adaptation to replication stress in cancer cells, we first aimed to identify the DNA repair genes associated with overall survival in cytogenetically normal AML” (CN-AML)
A list set of 175 genes involved in six major DNA repair pathways—ER, nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination repair (HRR), non-homologous end joining (NHEJ), and Fanconi (FANC) pathways—defined using the REPAIRtoire database and review of the literature (Table S1)

Summary

Introduction

Acute myeloid leukemia (AML) is the second most frequent type of adult leukemias. When analyzed with conventional cytogenetics, about 40–50% of AML exhibits no chromosomal abnormalities and are defined as “cytogenetically normal AML” (CN-AML) [1]. Mutated genes in CN-AML were identified, such as NPM1, signal transduction genes (FLT3), or myeloid transcription factor genes (CEBPA, RUNX1) [2]. Even if the study of the mutational landscape by new DNA sequencing technologies demonstrated a low mutation frequency in AML compared to other cancers [7], genomic instability remains a well-described leukemogenesis mechanism, illustrated by the high frequency of AML with non-random cytogenetics abnormalities or with complex karyotype [8,9]. Recurrent AML fusion transcripts such as RUNX1-RUNX1T1 or PML-RARA has been demonstrated to downregulate the expression of genes implied in DDR [11,12,13,14]. Dysregulation in DDR contributes to increased resistance to conventional chemotherapy by several mechanisms, such as paradoxically increased expression of DDR or cell cycle check-point genes [17,18,19]

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