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Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia.

Research paper by Alexa S AS Green, Thiago T TT Maciel, Marie-Anne MA Hospital, Chae C Yin, Fetta F Mazed, Elizabeth C EC Townsend, Sylvain S Pilorge, Mireille M Lambert, Etienne E Paubelle, Arnaud A Jacquel, Florence F Zylbersztejn, Justine J Decroocq, Laury L Poulain, Pierre P Sujobert, Nathalie N Jacque, et al.

Indexed on: 26 Nov '15Published on: 26 Nov '15Published in: Science advances



Abstract

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is frequently detected in acute myeloid leukemia (AML) patients and is associated with a dismal long-term prognosis. FLT3 tyrosine kinase inhibitors provide short-term disease control, but relapse invariably occurs within months. Pim protein kinases are oncogenic FLT3-ITD targets expressed in AML cells. We show that increased Pim kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. Ectopic Pim-2 expression induces resistance to FLT3 inhibition in both FLT3-ITD-induced myeloproliferative neoplasm and AML models in mice. Strikingly, we found that Pim kinases govern FLT3-ITD signaling and that their pharmacological or genetic inhibition restores cell sensitivity to FLT3 inhibitors. Finally, dual inhibition of FLT3 and Pim kinases eradicates FLT3-ITD(+) cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy.

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