title: Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.
abstract: The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [TKD1]) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5 [6%] of 84; 1 [3%] of 36). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD (internal tandem duplication), confers resistance to the FLT3 protein tyrosine kinase inhibitors (PTKIs) PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend toward a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in core-binding factor (CBF) leukemias and suggests a defined subgroup of CBF leukemias.
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich (LMU), Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Opatz
authors.forename: Harald
authors.initials: H
authors.lastname: Polzer
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.forename: Nikola P
authors.initials: NP
authors.lastname: Konstandin
authors.forename: Bianka
authors.initials: B
authors.lastname: Ksienzyk
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zellmeier
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.forename: Purvi M
authors.initials: PM
authors.lastname: Kakadia
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.forename: Annika
authors.initials: A
authors.lastname: Dufour
authors.forename: Jan
authors.initials: J
authors.lastname: Braess
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Sauerland
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Woermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D052160:Benzothiazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D050658:Core Binding Factor beta Subunit / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D015321:Gene Rearrangement; D006801:Humans; D007938:Leukemia / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics*
chemical_list: D052160:Benzothiazoles; C493692:CBFB protein, human; C095514:CBFbeta-MYH11 fusion protein; D050658:Core Binding Factor beta Subunit; D016207:Cytokines; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C544967:quizartinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin