title: Comprehensive mutational profiling of core binding factor acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years). Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.
authors.affiliation: Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France; Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, Lille, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duployez
authors.affiliation: Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France; Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, Lille, France;
authors.forename: Alice
authors.initials: A
authors.lastname: Marceau-Renaut
authors.affiliation: Department of Hematology, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.affiliation: Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France;
authors.forename: Arnaud
authors.initials: A
authors.lastname: Petit
authors.affiliation: Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France;
authors.forename: Maxime
authors.initials: M
authors.lastname: Bucci
authors.affiliation: Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France; Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, Lille, France;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Geffroy
authors.affiliation: Laboratory of Hematology, Trousseau Hospital, AP-HP, Paris, France;
authors.forename: Hélène
authors.initials: H
authors.lastname: Lapillonne
authors.affiliation: Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France; Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, Lille, France;
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.affiliation: Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France;
authors.forename: Christine
authors.initials: C
authors.lastname: Ragu
authors.affiliation: Functional and Structural Genomic Platform, Lille University, Lille, France;
authors.forename: Martin
authors.initials: M
authors.lastname: Figeac
authors.affiliation: Department of Hematology, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France;
authors.forename: Karine
authors.initials: K
authors.lastname: Celli-Lebras
authors.affiliation: Goelamsthèque, Cochin Hospital, AP-HP, Paris, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.affiliation: Department of Hematology, Gustave Roussy Institute, INSERM UMR 1170, Villejuif, France; Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY;
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.affiliation: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY;
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Laboratory of Hematology, CHU Reims, Reims, France;
authors.forename: Pascale
authors.initials: P
authors.lastname: Cornillet
authors.affiliation: Department of Hematology, CHU Angers, Angers, France; and.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: Department of Hematology, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France;
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France;
authors.forename: Guy
authors.initials: G
authors.lastname: Leverger
authors.affiliation: Department of Hematology, CHU Nîmes, Nîmes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.affiliation: Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France; Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, Lille, France;
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D007446:Chromosome Inversion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D050660:Core Binding Factors / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic; D055815:Young Adult; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D050676:Core Binding Factor Alpha 2 Subunit; D050660:Core Binding Factors; D004273:DNA, Neoplasm; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D000097722:Cohesins; C107844:AML1-ETO fusion protein, human; C095514:CBFbeta-MYH11 fusion protein