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;
Blood. 2013 Oct 3;122(14):2443-52. doi: 10.1182/blood-2013-03-491431. Epub 2013 Aug 27.
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.
急性髓系白血病 (AML) 是一种造血祖细胞的克隆性疾病，其特征是获得性异质性遗传改变，改变了正常的增殖、自我更新和分化机制。(1) 尽管 40% 至 45% 的 65 岁以下患者可以通过现有疗法治愈，但只有 10%的老年患者能够长期生存。(1) 由于在过去的 20 年中只有很少的新型 AML 药物获得批准，因此迫切需要确定新的靶点和治疗策略来治疗未得到满足的 AML 患者。我们在这里报告称，Axl，一种属于 Tyro3、Axl、Mer 受体酪氨酸激酶家族的成员，(2-4) 是 AML 的独立预后标志物和治疗靶点。AML 细胞通过骨髓基质细胞 (BMDSC) 诱导 Axl 配体生长停滞特异性基因 6 (Gas6) 的表达和分泌。Gas6 反过来介导表达 Axl 的 AML 细胞的增殖、存活和化疗耐药性。AML 细胞和 BMDSC 之间的这种 Gas6-Axl 旁分泌轴建立了一个具有化学保护作用的肿瘤细胞生态位，Axl 靶向方法可以破坏这种生态位。Axl 抑制在 FLT3 突变和 FLT3 野生型 AML 中均有效，改善了临床相关终点，其疗效取决于 Gas6 和 Axl 的存在。Axl 抑制单独或与化疗联合可能成为 AML 的一种新的治疗途径。
