title: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival.
abstract: Mutations in codon D816 of the KIT gene represent a recurrent genetic alteration in acute myeloid leukemia (AML). To clarify the biologic implication of activation loop mutations of the KIT gene, 1940 randomly selected AML patients were analyzed. In total, 33 (1.7%) of 1940 patients were positive for D816 mutations. Of these 33 patients, 8 (24.2%) had a t(8;21), which was significantly higher compared with the subgroup without D816 mutations. Analyses of genetic subgroups showed that KIT-D816 mutations were associated with t(8;21)/AML1-ETO and other rare AML1 translocations. In contrast, other activating mutations like FLT3 and NRAS mutations were very rarely detected in AML1-rearranged leukemia. KIT mutations had an independent negative impact on overall (median 304 vs 1836 days; P = .006) and event-free survival (median 244 vs 744 days; P = .003) in patients with t(8;21) but not in patients with a normal karyotype. The KIT-D816V receptor expressed in Ba/F3 cells was resistant to growth inhibition by the selective PTK inhibitors imatinib and SU5614 but fully sensitive to PKC412. Our findings clearly indicate that activating mutations of receptor tyrosine kinases are associated with distinct genetic subtypes in AML. The KIT-D816 mutations confer a poor prognosis to AML1-ETO-positive AML and should therefore be included in the diagnostic workup. Patients with KIT-D816-positive/AML1-ETO-positive AML might benefit from early intensification of treatment or combination of conventional chemotherapy with KIT PTK inhibitors.
authors.affiliation: Laboratory of Leukemia Diagnostics and Clinical Cooperative Group Leukemia, Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany. susanne.schnittger@mll-online.com
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Kohl
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.forename: Claudia
authors.initials: C
authors.lastname: Schoch
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D003062:Codon / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D017354:Point Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D012189:Retrospective Studies; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: C107844:AML1-ETO fusion protein, human; D003062:Codon; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D000075142:RUNX1 Translocation Partner 1 Protein; D019009:Proto-Oncogene Proteins c-kit