title: Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes.
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.
authors: Hematology Department, Institut Paoli Calmettes, Marseille, France.|Aix-Marseille University, Marseille, France.|Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.
authors: Raynier
authors: R
authors: Devillier
authors: Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors: Véronique
authors: V
authors: Mansat-De Mas
authors: Aix-Marseille University, Marseille, France.|Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.|Biopathology Department, Institut Paoli Calmettes, Marseille, France.
authors: Veronique
authors: V
authors: Gelsi-Boyer
authors: Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors: Cecile
authors: C
authors: Demur
authors: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.|Biopathology Department, Institut Paoli Calmettes, Marseille, France.
authors: Anne
authors: A
authors: Murati
authors: Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors: Jill
authors: J
authors: Corre
authors: Hematology Department, Institut Paoli Calmettes, Marseille, France.|Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.
authors: Thomas
authors: T
authors: Prebet
authors: Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
authors: Sarah
authors: S
authors: Bertoli
authors: Aix-Marseille University, Marseille, France.|Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.
authors: Mandy
authors: M
authors: Brecqueville
authors: Biopathology Department, Institut Paoli Calmettes, Marseille, France.
authors: Christine
authors: C
authors: Arnoulet
authors: Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.|Toulouse University, Toulouse, France.
authors: Christian
authors: C
authors: Recher
authors: Hematology Department, Institut Paoli Calmettes, Marseille, France.|Aix-Marseille University, Marseille, France.|Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.
authors: Norbert
authors: N
authors: Vey
authors: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.|Biopathology Department, Institut Paoli Calmettes, Marseille, France.
authors: Marie-Joelle
authors: MJ
authors: Mozziconacci
authors: Hematology Department, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.|Toulouse University, Toulouse, France.
authors: Eric
authors: E
authors: Delabesse
authors: Département d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, UMR1068 Inserm, Marseille, France.
authors: Daniel
authors: D
authors: Birnbaum
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000145:classification / Q000235:genetics* / Q000473:pathology; D000090243:Nucleophosmin; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; C000716967:NPM1 protein, human; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin
keywords: ASXL1; TP53; acute myeloid leukemia; mutational status; myelodysplasia-related changes