title: Acute myeloid leukemia with myelodysplasia-related changes are characterized by a specific molecular pattern with high frequency of ASXL1 mutations.
abstract: To determine whether the distinct and heterogeneous WHO category called "AML with myelodysplasia-related changes" (MRC-AML), presents specific molecular alterations we searched for mutations in genes known to be mutated in malignant myeloid diseases. In 48 MRC-AML patients analyzed, we found 17 mutations in ASXL1 (35%), eight in RUNX1 (17%), seven in TET2 (15%), 12 in IDH (n = 2) or IDH2 (n = 10) (25%), four in DNMT3A (8%), four in NPM1 (8%), and one in FLT3 (2%). Mutations were more frequent in the intermediate cytogenetic (IC) subgroup of 36 patients than in the unfavorable karyotype subgroup, with an average ratio mutations/patients of 1.36 [0-3] vs. 0.33 [0-2] (P < 0.001). Then, we compared these 36 patients with IC MRC-AML with a control panel of 37 no-MRC-AML patients, who had both IC and no dysplasia. IC MRC-AMLs were associated with higher incidence of ASXL1 mutations (47% vs. 0%, P < 0.001) and lower incidence of DNMT3A (6% vs. 38%, P = 0.001), NPM1 (11% vs. 62%, P < 0.001) and FLT3 (3% vs. 49%, P < 0.001) mutations. No difference was found in the incidence of IDH1/2 or TET2 mutations according to the presence of dysplasia. Complete remission rate after intensive treatment was lower in the MRC-AML group than in the no-MRC-AML group (48% vs. 78%, P = 0.023) and in wild type NPM1 patients (50% vs. 84%, P = 0.009). Our study showed that MRC-AML as defined in the WHO 2008 classification presents a specific mutation pattern characterized by a high frequency of ASXL1 mutations and a low rate of NPM1, FLT3, and DNMT3A mutations.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR Inserm, Institut Paoli-Calmettes, Marseille, France.
authors.forename: Raynier
authors.initials: R
authors.lastname: Devillier
authors.forename: Véronique
authors.initials: V
authors.lastname: Gelsi-Boyer
authors.forename: Mandy
authors.initials: M
authors.lastname: Brecqueville
authors.forename: Nadine
authors.initials: N
authors.lastname: Carbuccia
authors.forename: Anne
authors.initials: A
authors.lastname: Murati
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Daniel
authors.initials: D
authors.lastname: Birnbaum
authors.forename: Marie-Joëlle
authors.initials: MJ
authors.lastname: Mozziconacci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D021901:DNA, Intergenic / Q000737:chemistry*; D005260:Female; D005602:France; D056726:Genetic Association Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D012074:Remission Induction; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014944:World Health Organization; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: C473949:ASXL1 protein, human; D021901:DNA, Intergenic; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3