Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22).
AML1-MTG8 generated by t(8;21) contributes to leukemic transformation, but additional events are required for full leukemogenesis. We examined whether mutations in the receptor tyrosine kinase (RTK) pathway could be the genetic events that cause acute myeloblastic leukemia (AML) harboring t(8;21). Mutations in the second tyrosine kinase domain, juxtamembrane (JM) domain and exon 8 of the C-KIT gene were observed in 10, one and three of 37 AML patients with t(8;21), respectively. Three patients showed an internal tandem duplication in the JM domain of the FLT3 gene. One patient had a mutation in the K-Ras gene at codon 12. As the occurrence of these mutations was mutually exclusive, a total of 18 (49%) patients showed mutations in the RTK pathway. These results suggest that activating mutations in the RTK pathway play a role in part as an additional event leading to the development of t(8;21) AML. The 6-year cumulative incidence of relapse in patients with RTK pathway mutations was 79.8%, compared with 13.5% in patients lacking such mutations (P=0.0029). Furthermore, the 6-year relapse-free survival in patients with mutations was 18% compared to 60% in those without mutations (P=0.0340), indicating that RTK mutations are associated with the clinical outcome in t(8;21) AML.
Nanri
T
T
Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
Matsuno
N
N
Kawakita
T
T
Suzushima
H
H
Kawano
F
F
Mitsuya
H
H
Asou
N
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D018572:Disease-Free Survival; D005260:Female; D011905:Genes, ras; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D020080:Tandem Repeat Sequences; D014178:Translocation, Genetic; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3