|Budget Amount *help
¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1999 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1998 : ¥800,000 (Direct Cost : ¥800,000)
We carried out a screening analysis for internal tandem duplication of the FLT3 receptor gene (FLT3-ITD) in 180 patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and found several clinical characteristics as follows :
(1) FLT3-ITDs were identified in approximately 5% of patients with MDS, and were found more frequently in acute leukemia (20%). Mutant mRNA was expressed in all cases examined. In MDS, the frequency was higher in subtypes with excess of immature blasts, and we conclusively presume that this mutation is closely associated with leukemic transformation from MDS.
(2) Longitudinal analyses of the FLT3 gene configuration revealed that FLT3-ITD was late genetic alteration during the clinical course of MDS, as well as an N-RAS mutation. And these alterations did not show a relationship to specific chromosomal abnormalities.
(3) Among receptor tyrosine kinase type III genes (FLT3, KIT, PDGFR and CSF1R), the FLT3 gene solely showed ITDs in its juxtamembrane domain. And this novel type of mutation may positively influence proliferation of leukemic or myelodysplastic cells through elevation of kinase activity, based on undetermined mechanisms.
(4) The primers containing case-specific DNA sequences, generated by FLT3-ITD, allow us to amplify mutant FLT3 gene, resulting in appropriate detection of minimal residual disease in bone marrow samples or peripheral blood stem cells.
(5) Although the molecular basis of FLT3-ITD is not known well, the clinical manifestation of AML patients with mutant FLT3 was well delineated, and those with this alteration were revealed to show poor prognosis.
Further investigations are preferred to establish clinical and biological significance of this novel mutational event.