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

作者:Ben Batalla Isabel; Schultze Alexander; Wroblewski Mark; Erdmann Robert; Heuser Michael; Waizenegger Jonas S; Riecken Kristoffer; Binder Mascha; Schewe Denis; Sawall Stefanie; Witzke Victoria; Cubas Cordova Miguel; Janning Melanie; Wellbrock Jasmin; Fehse Boris; Hagel Christian; Krauter Juergen; Ganser Arnold; Lorens James B; Fiedler Walter; Carmeliet Peter; Pantel Klaus; Bokemeyer Carsten; Loges Sonja*
来源:Blood, 2013, 122(14): 2443-2452.
DOI:10.1182/blood-2013-03-491431

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.

  • 出版日期2013-10-3