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Sci Adv. 2015 Sep 18;1(8):e1500221. doi: 10.1126/sciadv.1500221. eCollection 2015 Sep.

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

Author information

1
Institut Cochin, Département Développement, Reproduction, Cancer, CNRS, UMR 8104, INSERM U1016, Paris 75014, France. ; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005, France. ; Equipe Labellisée, Ligue Nationale Contre le Cancer (LNCC), Paris 75013, France. ; Department of Hematology, Charles Nicolle University Hospital, Rouen 76000, France.
2
INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, Paris 75015, France. ; Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris 75015, France. ; CNRS ERL 8254, Paris 75015, France. ; Laboratory of Excellence GR-Ex, Paris 75015 , France.
3
Institut Cochin, Département Développement, Reproduction, Cancer, CNRS, UMR 8104, INSERM U1016, Paris 75014, France. ; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005, France. ; Equipe Labellisée, Ligue Nationale Contre le Cancer (LNCC), Paris 75013, France.
4
Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA 02115, USA.
6
Institut Cochin, Département Développement, Reproduction, Cancer, CNRS, UMR 8104, INSERM U1016, Paris 75014, France. ; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75005, France. ; Equipe Labellisée, Ligue Nationale Contre le Cancer (LNCC), Paris 75013, France. ; INSERM U1065/C3M Team 2, Cell Death Differentiation Inflammation and Cancer, Nice 06204, France.
7
INSERM U1065/C3M Team 2, Cell Death Differentiation Inflammation and Cancer, Nice 06204, France.
8
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.

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.

KEYWORDS:

AML; FLT3; Pim; tyrosine kinase inhibitors

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