Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes.

Raynier Devillier,Daniel Birnbaum,Mandy Brecqueville,Christine Arnoulet,Marie-Joelle Mozziconacci,Sarah Bertoli,Eric Delabesse,Norbert Vey,Jill Corre,Véronique Mansat-De Mas,Christian Recher,Thomas Prebet,Anne Murati,Cecile Demur,Veronique Gelsi-Boyer

doi:10.18632/oncotarget.3460

Abstract

Acute myeloid leukemias (AML) with myelodysplasia-related changes (AML-MRC) are defined by the presence of multilineage dysplasia (MLD), and/or myelodysplastic syndrome (MDS)-related cytogenetics, and/or previous MDS. The goal of this study was to identify distinct biological and prognostic subgroups based on mutations of ASXL1, RUNX1, DNMT3A, NPM1, FLT3 and TP53 in 125 AML-MRC patients according to the presence of MLD, cytogenetics and outcome. ASXL1 mutations (n=26, 21%) were associated with a higher proportion of marrow dysgranulopoiesis (mutant vs. wild-type: 75% vs. 55%, p=0.030) and were mostly found in intermediate cytogenetic AML (23/26) in which they predicted inferior 2-year overall survival (OS, mutant vs. wild-type: 14% vs. 37%, p=0.030). TP53 mutations (n=28, 22%) were mostly found in complex karyotype AML (26/28) and predicted poor outcome within unfavorable cytogenetic risk AML (mutant vs. wild-type: 9% vs. 40%, p=0.040). In multivariate analysis, the presence of either ASXL1 or TP53 mutation was the only independent factor associated with shorter OS (HR, 95%CI: 2.53, 1.40-4.60, p=0.002) while MLD, MDS-related cytogenetics and previous MDS history did not influence OS. We conclude that ASXL1 and TP53 mutations identify two molecular subgroups among AML-MRCs, with specific poor prognosis. This could be useful for future diagnostic and prognostic classifications.

Highlights

In the WHO 2008 classification, acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is defined as a distinct entity by the presence of multilineage dysplasia (MLD), and/or myelodysplastic syndrome (MDS)-related cytogenetics, and/or previously diagnosed MDS or MDS/Myeloproliferative neoplasm (MDS/MPN)[1]
We previously reported that Acute myeloid leukemias (AML) with MRC harbor a specific mutational profile with a high proportion of ASXL1 and RUNX1 mutations and less DNMT3A, FLT3 and NPM1 mutations than AMLs without criteria of AML-MRC[13]
In this series including only patients with AML-MRC, we have evaluated the correlation between these mutations and the different criteria defining AMLMRC

Summary

Introduction

In the WHO 2008 classification, acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is defined as a distinct entity by the presence of multilineage dysplasia (MLD), and/or myelodysplastic syndrome (MDS)-related cytogenetics, and/or previously diagnosed MDS or MDS/Myeloproliferative neoplasm (MDS/MPN)[1]. Gene mutations are a major tool for AML classification into distinct entities with specific prognosis[10,11,12], no molecular pattern is currently associated with AML-MRC. We hypothesized that the presence of mutations in targeted genes of interest could help identify subgroups of AML-MRC with distinct biological features and specific outcome. We report here a cohort of patients with AML-MRC for whom we analyzed the presence of mutational events according to AML-MRC criteria (MLD, cytogenetics and patient history) and identified mutationbased subgroups with specific poor outcome

Objectives

Methods

Results

Conclusion