title: Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML).
abstract: In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFalpha/beta genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P=0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P=0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (P<0.0001 and P=0.0002) owing to an excess of early events. c-Kit mutations were associated with a shorter EFS and RFS (P=0.002 and P=0.003) in t(8;21) but not inv(16) patients. As previously observed, Ras mutations did not affect prognosis. Screening for RTK mutations may help to identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or RTK inhibitors.
authors.affiliation: Service d'Hématologie Adulte, Hôpital Saint-Louis, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Boissel
authors.forename: H
authors.initials: H
authors.lastname: Leroy
authors.forename: B
authors.initials: B
authors.lastname: Brethon
authors.forename: N
authors.initials: N
authors.lastname: Philippe
authors.forename: S
authors.initials: S
authors.lastname: de Botton
authors.forename: A
authors.initials: A
authors.lastname: Auvrignon
authors.forename: E
authors.initials: E
authors.lastname: Raffoux
authors.forename: T
authors.initials: T
authors.lastname: Leblanc
authors.forename: X
authors.initials: X
authors.lastname: Thomas
authors.forename: O
authors.initials: O
authors.lastname: Hermine
authors.forename: B
authors.initials: B
authors.lastname: Quesnel
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.forename: G
authors.initials: G
authors.lastname: Leverger
authors.forename: H
authors.initials: H
authors.lastname: Dombret
authors.forename: C
authors.initials: C
authors.lastname: Preudhomme
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D050660:Core Binding Factors / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D007223:Infant; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D050660:Core Binding Factors; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; D016283:Proto-Oncogene Proteins p21(ras)