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

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.

• Authors: Alexa S Green, Thiago T Maciel, Marie-Anne Hospital, Chae Yin, Fetta Mazed, Elizabeth C Townsend, Sylvain Pilorge, Mireille Lambert, Etienne Paubelle, Arnaud Jacquel, Florence Zylbersztejn, Justine Decroocq, Laury Poulain, Pierre Sujobert, Nathalie Jacque, Kevin Adam, Jason C C So, Olivier Kosmider, Patrick Auberger, Olivier Hermine, David M Weinstock, Catherine Lacombe, Patrick Mayeux, Gary J Vanasse, Anskar Y Leung, Ivan C Moura, Didier Bouscary, Jerome Tamburini
• Journal: Science advances (Sci Adv) Vol. 1 Issue 8 Pg. e1500221 (Sep 2015) ISSN: 2375-2548 [Print] United States
• PMID: 26601252 (Publication Type: Journal Article)