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

Green, Alexa S; Maciel, Thiago T; Hospital, Marie-Anne; Yin, Chae; Mazed, Fetta; Townsend, Elizabeth C; Pilorge, Sylvain; Lambert, Mireille; Paubelle, Etienne; Jacquel, Arnaud; Zylbersztejn, Florence; Decroocq, Justine; Poulain, Laury; Sujobert, Pierre; Jacque, Nathalie; Adam, Kevin; So, Jason C C; Kosmider, Olivier; Auberger, Patrick; Hermine, Olivier; Weinstock, David M; Lacombe, Catherine; Mayeux, Patrick; Vanasse, Gary J; Leung, Anskar Y; Moura, Ivan C; Bouscary, Didier; Tamburini, Jerome

Green, Alexa S; Maciel, Thiago T; Hospital, Marie-Anne; Yin, Chae; Mazed, Fetta; Townsend, Elizabeth C; Pilorge, Sylvain; Lambert, Mireille; Paubelle, Etienne; Jacquel, Arnaud; Zylbersztejn, Florence; Decroocq, Justine; Poulain, Laury; Sujobert, Pierre; Jacque, Nathalie; Adam, Kevin; So, Jason C C; Kosmider, Olivier; Auberger, Patrick; Hermine, Olivier; Weinstock, David M; Lacombe, Catherine; Mayeux, Patrick; Vanasse, Gary J; Leung, Anskar Y; Moura, Ivan C; Bouscary, Didier; Tamburini, Jerome.

Afiliação

Green AS; 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. ; Depar
Maciel TT; 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
Hospital MA; 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.
Yin C; Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Mazed F; 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.
Townsend EC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA 02115, USA.
Pilorge S; 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. ; INSER
Lambert M; 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.
Paubelle E; 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
Jacquel A; INSERM U1065/C3M Team 2, Cell Death Differentiation Inflammation and Cancer, Nice 06204, France.
Zylbersztejn F; 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
Decroocq J; 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
Poulain L; 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.
Sujobert P; 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.
Jacque N; 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.
Adam K; 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.
So JC; Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Kosmider O; 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.
Auberger P; INSERM U1065/C3M Team 2, Cell Death Differentiation Inflammation and Cancer, Nice 06204, France.
Hermine O; 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
Weinstock DM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston 02115, MA 02115, USA.
Lacombe C; 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.
Mayeux P; 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.
Vanasse GJ; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
Leung AY; Division of Hematology, Department of Medicine, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Moura IC; 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
Bouscary D; 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.
Tamburini J; 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.

Sci Adv ; 1(8): e1500221, 2015 Sep.

Article em En | MEDLINE | ID: mdl-26601252

ABSTRACT

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.

Palavras-chave

AML; FLT3; Pim; tyrosine kinase inhibitors

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