title: ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome.
abstract: We aimed at evaluating ASXL1mut in 740 AML with intermediate risk karyotype for frequency, association with other mutations and impact on outcome. Five hundred fifty-three cases had a normal karyotype (NK) and 187 had intermediate risk aberrant cytogenetics. Overall, ASXL1mut were detected in 127/740 patients (17.2%). ASXL1mut were more frequent in males than in females (23.5% vs 9.9%, P<0.001). They were associated with higher age (median: 71.8 vs 61.8, P<0.001), a history of preceding myelodysplastic syndromes, and with a more immature immunophenotype compared with patients with wild-type ASXL1 (ASXL1wt). ASXL1mut were more frequent in patients with aberrant karyotype (58/187; 31.0%), especially in cases with trisomy 8 (39/74; 52.7%), than in those with NK (69/553; 12.5%; P<0.001). ASXL1mut were observed more frequent in RUNX1mut (P<0.001), and less frequent in NPM1mut (P<0.001), FLT3-internal tandem duplication (ITD) (P<0.001), FLT3-TKD (P=0.001) and DNMT3Amut (P<0.001). Patients with ASXL1mut had a shorter overall survival (OS) (P<0.001) and event free survival (P=0.012) compared with ASXL1wt. In multivariable analysis, ASXL1mut was an independent adverse factor for OS (P=0.032, relative risk: 1.70). In conclusion, ASXL1mut belong to the most frequent mutations in intermediate risk group AML. Their strong and independent dismal prognostic impact suggests the inclusion into the diagnostic work-up of AML.
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schnittger
authors.forename: C
authors.initials: C
authors.lastname: Eder
authors.forename: S
authors.initials: S
authors.lastname: Jeromin
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.forename: A
authors.initials: A
authors.lastname: Fasan
authors.forename: V
authors.initials: V
authors.lastname: Grossmann
authors.forename: A
authors.initials: A
authors.lastname: Kohlmann
authors.forename: T
authors.initials: T
authors.lastname: Illig
authors.forename: N
authors.initials: N
authors.lastname: Klopp
authors.forename: H-E
authors.initials: HE
authors.lastname: Wichmann
authors.forename: K-A
authors.initials: KA
authors.lastname: Kreuzer
authors.forename: C
authors.initials: C
authors.lastname: Schmid
authors.forename: P
authors.initials: P
authors.lastname: Staib
authors.forename: R
authors.initials: R
authors.lastname: Peceny
authors.forename: N
authors.initials: N
authors.lastname: Schmitz
authors.forename: W
authors.initials: W
authors.lastname: Kern
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D005091:Exons / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C000717967:DNMT3A protein, human; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3