title: 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.affiliation: 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.
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.affiliation: 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.
authors.forename: Thiago T
authors.initials: TT
authors.lastname: Maciel
authors.affiliation: 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.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Hospital
authors.affiliation: Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chae
authors.initials: C
authors.lastname: Yin
authors.affiliation: 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.
authors.forename: Fetta
authors.initials: F
authors.lastname: Mazed
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA 02115, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Townsend
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pilorge
authors.affiliation: 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.
authors.forename: Mireille
authors.initials: M
authors.lastname: Lambert
authors.affiliation: 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.
authors.forename: Etienne
authors.initials: E
authors.lastname: Paubelle
authors.affiliation: INSERM U1065/C3M Team 2, Cell Death Differentiation Inflammation and Cancer, Nice 06204, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquel
authors.affiliation: 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.
authors.forename: Florence
authors.initials: F
authors.lastname: Zylbersztejn
authors.affiliation: 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.
authors.forename: Justine
authors.initials: J
authors.lastname: Decroocq
authors.affiliation: 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.
authors.forename: Laury
authors.initials: L
authors.lastname: Poulain
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sujobert
authors.affiliation: 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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacque
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Adam
authors.affiliation: Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Jason C C
authors.initials: JC
authors.lastname: So
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.affiliation: INSERM U1065/C3M Team 2, Cell Death Differentiation Inflammation and Cancer, Nice 06204, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA 02115, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Vanasse
authors.affiliation: Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Anskar Y
authors.initials: AY
authors.lastname: Leung
authors.affiliation: 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.
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.affiliation: 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.
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
authors.affiliation: 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.
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
keywords: AML; FLT3; Pim; tyrosine kinase inhibitors