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

被引：72

作者：

Green, Alexa S. ^{[1
,2
,3
,4
]}

Maciel, Thiago T. ^{[5
,6
,7
,8
]}

Hospital, Marie-Anne ^{[1
,2
,3
]}

Yin, Chae ^{[9
]}

Mazed, Fetta ^{[1
,2
,3
]}

Townsend, Elizabeth C. ^{[10
]}

Pilorge, Sylvain ^{[1
,2
,3
,11
]}

Lambert, Mireille ^{[1
,2
,3
]}

Paubelle, Etienne ^{[5
,6
,7
,8
]}

Jacquel, Arnaud ^{[11
]}

Zylbersztejn, Florence ^{[5
,6
,7
,8
]}

Decroocq, Justine ^{[5
,6
,7
,8
]}

Poulain, Laury ^{[1
,2
,3
]}

Sujobert, Pierre ^{[1
,2
,3
]}

Jacque, Nathalie ^{[1
,2
,3
]}

Adam, Kevin ^{[1
,2
,3
]}

So, Jason C. C. ^{[9
]}

Kosmider, Olivier ^{[1
,2
,3
]}

Auberger, Patrick ^{[11
]}

Hermine, Olivier ^{[5
,6
,7
,8
]}

Weinstock, David M. ^{[10
]}

Lacombe, Catherine ^{[1
,2
,3
]}

Mayeux, Patrick ^{[1
,2
,3
]}

Vanasse, Gary J. ^{[12
]}

Leung, Anskar Y. ^{[9
]}

Moura, Ivan C. ^{[5
,6
,7
,8
]}

Bouscary, Didier ^{[1
,2
,3
]}

Tamburini, Jerome ^{[1
,2
,3
]}

机构：

[1] CNRS, Inst Cochin, INSERM U1016, Dept Dev Reprod Canc,UMR 8104, F-75014 Paris, France

[2] Univ Paris 05, Fac Med, Sorbonne Paris Cite, F-75005 Paris, France

[3] Ligue Natl Canc LNCC, Equipe Labellisee, F-75013 Paris, France

[4] Charles Nicolle Univ Hosp, Dept Hematol, F-76000 Rouen, France

[5] INSERM UMR 1163, Lab Cellular & Mol Mech Hematol Disorders & Thera, F-75015 Paris, France

[6] Paris Descartes Sorbonne Paris Cite Univ, Imagine Inst, F-75015 Paris, France

[7] CNRS, ERL 8254, F-75015 Paris, France

[8] Lab Excellence GR Ex, F-75015 Paris, France

[9] Univ Hong Kong, Li Ka Shing LKS Fac Med, Dept Med, Div Hematol, Hong Kong, Hong Kong, Peoples R China

[10] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[11] INSERM U1065, C3M Team 2, Cell Death Differentiat Inflammat & Canc, F-06204 Nice, France

[12] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

来源：

SCIENCE ADVANCES | 2015年 / 1卷 / 08期

关键词：

D O I：

10.1126/sciadv.1500221

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 shortterm 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 FLT3ITD- 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 Pimkinases eradicates FLT3-ITD+ cells including primary AML cells. Concomitant Pim and FLT3 inhibition represents a promising new avenue for AML therapy.

引用

页数：13