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Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia

Leukemia volume 18, pages 466–475 (2004)Cite this article

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.

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Acknowledgements

We thank Mr Ching-Tai Lee, Ms Chang-Liang Lai, Ms Meng-Chu Chou, Ms Chiu-Shia Shu and Ms Siew-Hoon Teoh for technical assistance, and Ms Yu-Feng Wang for secretarial assistance. This work was supported by Grants NSC89-2314-B182-120, NSC90-2314-B-182-086 and NSC91-2314-B-182-032 from the National Science Council, Taiwan.

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  1. Department of Internal Medicine, Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taipei, Taiwan

    L-Y Shih, C-F Huang, P-N Wang, J-H Wu, T-L Lin, P Dunn & M-C Kuo

  2. School of Medicine, Chang Gung University, Taoyuan, Taiwan

    L-Y Shih & P Dunn

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Correspondence to L-Y Shih.

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Shih, LY., Huang, CF., Wang, PN. et al. Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia 18, 466–475 (2004). https://doi.org/10.1038/sj.leu.2403274

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