Journal
BLOOD
Volume 122, Issue 14, Pages 2443-2452Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-03-491431
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Funding
- Max-Eder group leader program from Deutsche Krebshilfe
- Deutsche Forschungsgemeinschaft [LO1863/3-1]
- Medical Faculty of the University of Hamburg (FFM program)
- Hamburger Exzellenzinitiative (LEXI program)
- Roggenbuck Stiftung
- Hamburger Krebsgesellschaft
- Hubertus-Wald fellowship
- ERC Advanced Investigator Grant [269081]
- European Research Council (ERC) [269081] Funding Source: European Research Council (ERC)
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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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