Abstract
AXL belongs to the TAM (TYRO3, AXL, and MERTK) receptor family, a unique subfamily of the receptor tyrosine kinases. Their common ligand is growth arrest-specific protein 6 (GAS6). The GAS6/TAM signaling pathway regulates many important cell processes and plays an essential role in immunity, hemostasis, and erythropoiesis. In cancer, AXL overexpression and activation has been associated with cell proliferation, chemotherapy resistance, tumor angiogenesis, invasion, and metastasis; and has been correlated with a poor prognosis. In hematological malignancies, the expression and function of AXL is highly diverse, not only between the different tumor types but also in the surrounding tumor microenvironment. Most research and clinical evidence has been provided for AXL inhibitors in acute myeloid leukemia. However, recent studies also revealed an important role of AXL in lymphoid leukemia, lymphoma, and multiple myeloma. In this review, we summarize the basic functions of AXL in various cell types and the role of AXL in different hematological cancers, with a focus on AXL in the dormancy of multiple myeloma. In addition, we provide an update on the most promising AXL inhibitors currently in preclinical/clinical evaluation and discuss future perspectives in this emerging field.
Highlights
AXL was first detected as an unidentified transforming gene in two chronic myeloid leukemia patients in 1988 [1]
The number of growth arrest-specific protein 6 (GAS6)+ and Mer proto-oncogene tyrosine kinase (MERTK)+ bone marrow plasma cells (BMPCs) were significantly increased in myeloma patients compared to healthy controls; whereas AXL and Tyrosine kinase receptor 3 (TYRO3) were mainly undetectable in BMPCs of both groups and in human myeloma cell lines
They demonstrated that Axl, macrophage-expressed gene 1 (Mpeg1), and signal regulatory protein α (Sirpα) expression could be induced by direct contact with osteoblasts in vitro
Summary
AXL ( known as UFO, TYRO7, ARK) was first detected as an unidentified transforming gene in two chronic myeloid leukemia patients in 1988 [1]. AXL is a driver of diverse cellular processes involved in cancer pathogenesis including proliferation, survival, migration, metastasis, dormancy and chemoresistance. Increased AXL expression has been detected in a variety of solid tumors (e.g., prostate cancer, breast cancer, osteosarcoma, etc.) and hematological malignancies including chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma and mantle cell lymphoma. We will discuss the basic function of AXL, its major role in controlling the immune system in a normal and cancerous setting, how it contributes to cancer pathogenesis and focus on the role of AXL in hematological malignancies. Cancers 2019, 11, 1727 of which the majority are non-specific multi-kinase inhibitors, in a preclinical or clinical setting for hematological cancers will be provided as well
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