Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma - PubMed (original) (raw)
. 2013 Oct 3;122(14):2443-52.
doi: 10.1182/blood-2013-03-491431. Epub 2013 Aug 27.
Alexander Schultze, Mark Wroblewski, Robert Erdmann, Michael Heuser, Jonas S Waizenegger, Kristoffer Riecken, Mascha Binder, Denis Schewe, Stefanie Sawall, Victoria Witzke, Miguel Cubas-Cordova, Melanie Janning, Jasmin Wellbrock, Boris Fehse, Christian Hagel, Jürgen Krauter, Arnold Ganser, James B Lorens, Walter Fiedler, Peter Carmeliet, Klaus Pantel, Carsten Bokemeyer, Sonja Loges
Affiliations
- PMID: 23982172
- DOI: 10.1182/blood-2013-03-491431
Free article
Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma
Isabel Ben-Batalla et al. Blood. 2013.
Free article
Abstract
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.
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