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

Authors
  • Green, A. S.
  • Maciel, T. T.
  • Hospital, M.-A.
  • Yin, C.
  • Mazed, F.
  • Townsend, E. C.
  • Pilorge, S.
  • Lambert, M.
  • Paubelle, E.
  • Jacquel, A.
  • Zylbersztejn, F.
  • Decroocq, J.
  • Poulain, L.
  • Sujobert, P.
  • Jacque, N.
  • Adam, K.
  • So, J. C. C.
  • Kosmider, O.
  • Auberger, P.
  • Olivier Hermine
  • And 8 more
Type
Published Article
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Publication Date
Jul 27, 2015
Volume
1
Issue
8
Identifiers
DOI: 10.1126/sciadv.1500221
PMID: 26601252
PMCID: PMC4643770
Source
USPC - SET - SVS
License
Green

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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