title: Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma.
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.
authors: Department of Hematology, Oncology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors: Isabel
authors: I
authors: Ben-Batalla
authors: Alexander
authors: A
authors: Schultze
authors: Mark
authors: M
authors: Wroblewski
authors: Robert
authors: R
authors: Erdmann
authors: Michael
authors: M
authors: Heuser
authors: Jonas S
authors: JS
authors: Waizenegger
authors: Kristoffer
authors: K
authors: Riecken
authors: Mascha
authors: M
authors: Binder
authors: Denis
authors: D
authors: Schewe
authors: Stefanie
authors: S
authors: Sawall
authors: Victoria
authors: V
authors: Witzke
authors: Miguel
authors: M
authors: Cubas-Cordova
authors: Melanie
authors: M
authors: Janning
authors: Jasmin
authors: J
authors: Wellbrock
authors: Boris
authors: B
authors: Fehse
authors: Christian
authors: C
authors: Hagel
authors: Jürgen
authors: J
authors: Krauter
authors: Arnold
authors: A
authors: Ganser
authors: James B
authors: JB
authors: Lorens
authors: Walter
authors: W
authors: Fiedler
authors: Peter
authors: P
authors: Carmeliet
authors: Klaus
authors: K
authors: Pantel
authors: Carsten
authors: C
authors: Bokemeyer
authors: Sonja
authors: S
authors: Loges
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D019899:Paracrine Communication / Q000502:physiology*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000970:Antineoplastic Agents; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6