Abstract
A GAS6–AXL signaling axis creates a chemoprotective niche for acute myeloid leukemia (AML).
Major finding: A GAS6–AXL signaling axis creates a chemoprotective niche for acute myeloid leukemia (AML).
Concept: AML cells induce GAS6 secretion by stromal cells, which activates AXL signaling in AML cells.
Impact: AXL inhibitors may be effective alone or in combination with chemotherapy in some patients with AML.
The AXL receptor tyrosine kinase and its ligand growth arrest-specific 6 (GAS6) are upregulated in many human cancers and have been implicated in cancer cell survival and drug resistance. Ben-Batalla and colleagues found that AXL and GAS6 are expressed in 57% and 90% of patients with cytogenetically normal AML, respectively, and that AXL overexpression is an independent prognostic factor for shorter overall survival. AXL was also more highly expressed in the bone marrow, mononucleated cells, blasts, and leukemic stem cells of patients with AML compared with those of healthy control subjects, but expression levels of GAS6 were indistinguishable in AML and normal cells. Instead, GAS6 expression was specifically increased in bone marrow–derived stromal cells (BMDSC) from AML patients compared with control BMDSCs. Coculture of AML cells with BMDSCs revealed that AML cells induced secretion of GAS6 by BMDSCs in an interleukin-10– and macrophage colony-stimulating factor–dependent manner, suggesting that AML cells educate BMDSCs to produce GAS6. In turn, BMDSC-produced GAS6 promoted survival and chemoprotection of AXL-expressing AML cells. A small-molecule AXL inhibitor suppressed growth and increased chemosensitivity only in AML cells that expressed both AXL and GAS6. However, the cytotoxic effects of AXL inhibition could be restored in resistant GAS6-negative AML cells by coculture with GAS6-secreting BMDSCs, indicating that both autocrine and paracrine activation of AXL by GAS6 can promote survival and chemoresistance in AML cells. AXL inhibitor monotherapy prolonged survival and inhibited tumor growth in in several AML xenograft models and led to regression of established tumors at the highest dose tested. Combined use of subtherapeutic doses of the AXL inhibitor and doxorubicin also inhibited tumor growth, raising the possibility that blockade of AXL-driven resistance mechanisms may potentiate the effects of chemotherapeutic agents in AML. Collectively, these findings suggest that targeting the GAS6–AXL signaling axis may benefit a subset of patients with AML.
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