Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma
Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma
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DOI：
10.1182/blood-2013-03-491431
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发表时间：
2013-10-03
期刊：
影响因子：
20.3
通讯作者：
Loges, Sonja
中科院分区：
文献类型：
--
作者：
Ben-Batalla, Isabel;Schultze, Alexander;Loges, Sonja
急性髓性白血病（AML）是一种造血祖细胞的克隆性疾病，其特征是获得性异质遗传改变，改变正常的增殖、自我更新和分化机制。(1) 65岁以下的患者，目前的治疗方法可以治愈40% - 45%的患者，但只有10%的老年患者达到长期生存。(1)由于在过去的20年里只有很少的新型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治疗不足的AML患者。我们在这里报道，Axl是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细胞诱导骨髓源性基质细胞（bmmdscs）表达和分泌Axl配体生长阻滞特异性基因6 （Gas6）。反过来，Gas6介导表达axl的AML细胞的增殖、存活和化疗耐药。AML细胞和BMDSCs之间的Gas6-Axl旁分泌轴建立了一个化学保护性肿瘤细胞生态位，可以被axl靶向方法所消除。Axl抑制在FLT3突变型和FLT3野生型AML中具有活性，改善临床相关终点，其疗效取决于Gas6和Axl的存在。单独抑制Axl或联合化疗可能是AML的一种新的治疗途径。
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.