Role ofASXL1andTP53mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes

// Raynier Devillier 1,2,3 , Véronique Mansat-De Mas 5,* , Veronique Gelsi-Boyer 2,3,4,* , Cecile Demur 5,* , Anne Murati 3,4,* , Jill Corre 5,* , Thomas Prebet 1,3 , Sarah Bertoli 5 , Mandy Brecqueville 2,3 , Christine Arnoulet 4 , Christian Recher 5,6 , Norbert Vey 1,2,3 , Marie-Joelle Mozziconacci 3,4 , Eric Delabesse 5,6 and Daniel Birnbaum 3 1 Hematology Department, Institut Paoli Calmettes, Marseille, France 2 Aix-Marseille University, Marseille, France 3 Département d’Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France 4 Biopathology Department, Institut Paoli Calmettes, Marseille, France 5 Hematology Department, Institut Universitaire du Cancer Toulouse–Oncopole, Toulouse, France 6 Toulouse University, Toulouse, France * These authors contributed equally to this work Correspondence to: Raynier Devillier, email: // Keywords : acute myeloid leukemia, myelodysplasia-related changes, mutational status, ASXL1, TP53 Received : September 24, 2014 Accepted : January 20, 2015 Published : February 28, 2015 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.