AML1-MTG8 generated by t(8;21)(q22:q22) contributes to leukemic transformation but additional events are required for full leukemogenesis. Mutations in the receptor tyrosine kinase (RTK) including C-KIT and FLT3 genes appear to be the genetic events that cause acute myeloid leukemia (AML) harboring t(8;21) and are associated with unfavorable prognosis (

Nanri et al. Leukemia 19:1361;2005
). On the other hand, the activating V617F mutation in the JAK2 cytoplasmic tyrosine kinase has been detected in a significant proportion of patients with myeloproliferative disorders. Although the same mutation has been identified in a small number of AML patients, it is likely that a relatively high incidence of JAK2-V617F mutation has been seen in t(8;21) AML patients. However, whether they are associated with other biological parameters and whether they influence clinical prognosis in patients with t(8;21) AML have not been determined. To clarify the biological and prognostic impact of the JAK2 mutation, we examined the clinical and prognostic relevance of the mutation. Of 45 patients with t(8;21) AML, mutations in the C-KIT and internal tandem duplications (ITD) in the FLT3 were observed in 18 (40%) and 3 (6.7%), respectively. We detected the JAK2-V617F mutation in 3 patients with t(8;21) AML (6.7%), which was consistent with previous studies. Although the occurrence of C-KIT and FLT3 mutations was mutually exclusive, one patient harboring JAK2 mutation also had a C-KIT second tyrosine kinase mutation and another one patient had a K-RAS mutation. Collectively, a total of 23 (51%) patients showed mutations in the RTK pathway. One patient carrying both C-KIT and JAK2 mutations did not respond to multiple induction chemotherapies. Another patient with the JAK2 and K-RAS mutations achieved a complete remission (CR) but later relapsed. Remaining one patient received allogeneic stem cell transplantation during first CR and continued CR. As we were limited to study a small number of mutated cases for a comparison of clinical and genetic features, we examined the clinical significance of C-KIT, FLT3 and JAK2 mutations as a collective group. A cumulative incidence of relapse (CIR) in 21 patients with RTK mutations was 77%, whereas CIR in 19 patients lacking mutations was 26% (P=0.0083). The 6-year relapse-free survival in patients with mutations was 20% compared to 54% in those without mutations (P=0.0595). These results suggest that the mutations in the JAK2, C-KIT and FLT3 could be an additional genetic events leading to the development of AML and are associated with the clinical outcome in patients with t(8;21) AML.

Topics:
flt3 gene, jak2 gene v617f, leukemia, myelocytic, acute, ms-like tyrosine kinase 3, mutation, proto-oncogene protein c-kit, treatment outcome, protein tyrosine kinase, allogeneic stem cell transplant, chemotherapy regimen

Author notes

Disclosure: No relevant conflicts of interest to declare.

2007, The American Society of Hematology
2007
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