1. Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia
- Author
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Alexa S. Green, Florence Zylbersztejn, Mireille Lambert, Thiago Trovati Maciel, Ivan C. Moura, Patrick Auberger, Pierre Sujobert, Sylvain Pilorge, Elizabeth C. Townsend, Fetta Mazed, Catherine Lacombe, Justine Decroocq, Olivier Hermine, Olivier Kosmider, Patrick Mayeux, David M. Weinstock, Didier Bouscary, Etienne Paubelle, Chae Yin, Gary J. Vanasse, Laury Poulain, Nathalie Jacque, Arnaud Jacquel, Jerome Tamburini, Kevin Adam, Jason C. C. So, and Anskar Y.H. Leung
- Subjects
Internal tandem duplication ,03 medical and health sciences ,0302 clinical medicine ,fluids and secretions ,AML ,hemic and lymphatic diseases ,tyrosine kinase inhibitors ,Medicine ,FLT3 ,Myeloproliferative neoplasm ,Research Articles ,030304 developmental biology ,Cell sensitivity ,0303 health sciences ,Multidisciplinary ,business.industry ,Kinase ,Myeloid leukemia ,SciAdv r-articles ,hemic and immune systems ,medicine.disease ,3. Good health ,Pim ,Pim kinases ,030220 oncology & carcinogenesis ,Immunology ,embryonic structures ,Cancer research ,business ,Tyrosine kinase ,psychological phenomena and processes ,Flt3 itd ,Research Article ,Signal Transduction - Abstract
Synergy between FLT3 and Pim kinase inhibition in acute myeloid leukemia with FLT3-ITD mutation., 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.
- Published
- 2015