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Therapy-Related Leukemias

Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia

Leukemia volume 19, pages 2232–2240 (2005)Cite this article

Abstract

Mutations of the FLT3, c-KIT, c-FMS, KRAS, NRAS, BRAF and CEBPA genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal-transduction pathway are frequent in acute myeloid leukemia (AML). We examined 140 patients with therapy-related myelodysplasia or AML (t-MDS/t-AML) for point mutations of these seven genes. In all, 11 FLT3, two c-KIT, seven KRAS, eight NRAS and three BRAF mutations were identified in 29 patients (21%). All but one patient with a FLT3 mutation presented with t-AML (P=0.0002). Furthermore, FLT3 mutations were significantly associated with previous radiotherapy without chemotherapy (P=0.03), and with a normal karyotype (P=0.004), but inversely associated with previous therapy with alkylating agents (P=0.003) and with −7/7q− (P=0.001). RAS mutations were associated with AML1 point mutations (P=0.046) and with progression from t-MDS to t-AML (P=0.008). Noteworthy, all three patients with BRAF mutations presented as t-AML of M5 subtype with t(9;11)(p22;q23) and MLL-rearrangement (P=0.01). In t-AML RAS/BRAF mutations were significantly associated with a very short survival (P=0.017). Half of the patients with a mutation in the RTK/RAS-BRAF signal-transduction pathway (denoted ‘class-I’ mutations) simultaneously disclosed mutation of a hematopoietic transcription factor (denoted ‘class-II’ mutations) (P=0.046) suggesting their cooperation in leukemogenesis.

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Acknowledgements

The authors are indebted to Pia Bech and Vivian Jensen for excellent technical assistance in the molecular studies and to Inge-Lise Frost Andersen for excellent technical assistance in the FISH analyses. Supported by grants from the Danish Cancer Society.

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  1. Department of Clinical Genetics, Section of Hematology/Oncology 4052, Juliane Marie Center, Rigshospitalet, Copenhagen, Denmark

    D H Christiansen, M K Andersen, F Desta & J Pedersen-Bjergaard

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Correspondence to D H Christiansen.

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Christiansen, D., Andersen, M., Desta, F. et al. Mutations of genes in the receptor tyrosine kinase (RTK)/RAS-BRAF signal transduction pathway in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia 19, 2232–2240 (2005). https://doi.org/10.1038/sj.leu.2404009

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