title: Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia.
abstract: The role of internal tandem duplication of fms-like tyrosine kinase 3 (FLT3/ITD), mutations at tyrosine kinase domain (FLT3/TKD) and N-ras mutations in the transformation of myelodysplastic syndrome (MDS) to AML was investigated in 82 MDS patients who later progressed to AML; 70 of them had paired marrow samples at diagnosis of MDS and AML available for comparative analysis. Five of the 82 patients had FLT3/ITD at presentation. Of the 70 paired samples, seven patients acquired FLT3/ITD during AML evolution. The incidence of FLT3/ITD at diagnosis of MDS was significantly lower than that at AML transformation (3/70 vs 10/70, P<0.001). FLT3/ITD(+) patients progressed to AML more rapidly than FLT3/ITD(-) patients (2.5+/-0.5 vs 11.9+/-1.5 months, P=0.114). FLT3/ITD(+) patients had a significantly shorter survival than FLT3/ITD(-) patients (5.6+/-1.3 vs 18.0+/-1.7 months, P=0.0008). After AML transformation, FLT3/ITD was also associated with an adverse prognosis. One patient had FLT3/TKD mutation (D835Y) at both MDS and AML stages. Additional three acquired FLT3/TKD (one each with D835 H, D835F and I836S) at AML transformation. Five of the 70 matched samples had N-ras mutation at diagnosis of MDS compared to 15 at AML transformation (P<0.001), one lost and 11 gained N-ras mutations at AML progression. Coexistence of FLT3/TKD and N-ras mutations was found in two AML samples. N-ras mutations had no prognostic impact either at the MDS or AML stage. Our results show that one-third of MDS patients acquire activating mutations of FLT3 or N-ras gene during AML evolution and FLT3/ITD predicts a poor outcome in MDS.
authors.affiliation: Department of Internal Medicine, Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan. sly7012@adm.cgmh.org.tw
authors.forename: L-Y
authors.initials: LY
authors.lastname: Shih
authors.forename: C-F
authors.initials: CF
authors.lastname: Huang
authors.forename: P-N
authors.initials: PN
authors.lastname: Wang
authors.forename: J-H
authors.initials: JH
authors.lastname: Wu
authors.forename: T-L
authors.initials: TL
authors.lastname: Lin
authors.forename: P
authors.initials: P
authors.lastname: Dunn
authors.forename: M-C
authors.initials: MC
authors.lastname: Kuo
mesh_terms: D000208:Acute Disease; D001853:Bone Marrow / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3