Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma

被引:180
作者
Ben-Batalla, Isabel [1 ,2 ]
Schultze, Alexander [1 ,2 ]
Wroblewski, Mark [1 ,2 ]
Erdmann, Robert [1 ,2 ]
Heuser, Michael [3 ]
Waizenegger, Jonas S. [1 ,2 ]
Riecken, Kristoffer [4 ]
Binder, Mascha [1 ]
Schewe, Denis [5 ]
Sawall, Stefanie [1 ,2 ]
Witzke, Victoria [1 ,2 ]
Cubas-Cordova, Miguel [1 ,2 ]
Janning, Melanie [1 ,2 ]
Wellbrock, Jasmin [1 ]
Fehse, Boris [4 ]
Hagel, Christian [6 ]
Krauter, Juergen [3 ]
Ganser, Arnold [3 ]
Lorens, James B. [7 ,8 ]
Fiedler, Walter [1 ]
Carmeliet, Peter [9 ,10 ]
Pantel, Klaus [2 ]
Bokemeyer, Carsten [1 ]
Loges, Sonja [1 ,2 ]
机构
[1] Univ Med Ctr Hamburg Eppendorf, Univ Comprehens Canc Ctr Hamburg, Oncol & Bone Marrow Transplantat Sect Pneumol, Dept Hematol,Hubertus Wald Tumorzentrum, D-20246 Hamburg, Germany
[2] Univ Med Ctr Hamburg Eppendorf, Dept Tumor Biol, Ctr Med Expt, D-20246 Hamburg, Germany
[3] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover, Germany
[4] Univ Med Ctr Hamburg Eppendorf, Res Dept Cell & Gene Therapy, Clin Stem Cell Transplantat, Univ Canc Ctr Hamburg, D-20246 Hamburg, Germany
[5] Univ Med Ctr Schleswig Holstein, Dept Pediat, Kiel, Germany
[6] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, D-20246 Hamburg, Germany
[7] Univ Bergen, Dept Biomed, Bergen, Norway
[8] Univ Bergen, Ctr Canc Biomarkers, Bergen, Norway
[9] VIB, Lab Angiogenesis & Neurovasc Link, Vesalius Res Ctr, Louvain, Belgium
[10] Katholieke Univ Leuven, Lab Angiogenesis & Neurovasc Link, Vesalius Res Ctr, Louvain, Belgium
基金
欧洲研究理事会;
关键词
RECEPTOR TYROSINE KINASE; ARREST-SPECIFIC GENE-6; ONTOLOGY LEGO VECTORS; PROLONGS SURVIVAL; TUMOR-GROWTH; GAS6; INHIBITION; EXPRESSION; APOPTOSIS; BLOCKS;
D O I
10.1182/blood-2013-03-491431
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML.
引用
收藏
页码:2443 / 2452
页数:10
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