Autotaxin is expressed in FLT3-ITD positive acute myeloid leukemia and hematopoietic stem cells and promotes cell migration and proliferation
Autotaxin is expressed in FLT3-ITD positive acute myeloid leukemia and hematopoietic stem cells and promotes cell migration and proliferation
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DOI：
10.1016/j.exphem.2013.01.007
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发表时间：
2013-05-01
影响因子：
2.6
通讯作者：
Thiede, Christian
中科院分区：
文献类型：
--
作者：
Ortlepp, Claudia;Steudel, Christine;Thiede, Christian
Autotaxin （ATX）已被报道为多种癌细胞的运动和生长因子。ATX蛋白作为分泌的溶血磷脂酶D，将溶血磷脂酰胆碱（LPC）转化为溶血磷脂酸（LPA），通过g蛋白偶联受体发出信号，在细胞迁移和增殖中具有重要功能。本研究表明，在FLT3受体基因内部串联重复（ITD）突变的急性髓性白血病（AML）中，ATX的表达特异性上调，并具有功能活性。此外，ATX在正常人CD34+祖细胞和选定的髓系和淋巴亚群中也有表达。在选定的细胞系中，通过逆转录病毒载体转导强制表达突变体FLT3-ITD增加了ATX mRNA，而通过亚致死剂量的PKC412或SU5614抑制FLT3-ITD信号传导导致ATX mRNA和蛋白水平显著下调。在LPC存在的情况下，ATX的表达显著增加了细胞的增殖。LPA在所有测试的人白血病细胞系和人CD34+祖细胞中诱导增殖，而不考虑ATX的表达，并诱导趋化。LPC仅在内源性ATX高表达的细胞中增加了至少80%的趋化性，证明了ATX的自分泌作用。使用小分子抑制剂抑制ATX选择性地诱导杀死表达ATX的细胞系并降低这些细胞的运动性。我们的数据表明，通过ATX产生的生物活性LPA参与控制造血过程中的增殖和迁移，而ATX的失调有助于AML的发病机制。(C) 2013 ISEH -血液学与干细胞学会。Elsevier Inc.出版。
Autotaxin (ATX) has been reported to act as a motility and growth factor in a variety of cancer cells. The ATX protein acts as a secreted lysophospholipase D by converting lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which signals via G-protein coupled receptors and has important functions in cell migration and proliferation. This study demonstrates that ATX expression is specifically upregulated and functionally active in acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) mutation of the FLT3 receptor gene. Moreover, ATX expression was also found in normal human CD34+ progenitor cells and selected myeloid and lymphoid subpopulations. Enforced expression of mutant FLT3-ITD by retroviral vector transduction increased ATX mRNA in selected cell lines, whereas inhibition of FLT3-ITD signaling by sublethal doses of PKC412 or SU5614 led to a significant down-regulation of ATX mRNA and protein levels. In the presence of LPC, ATX expression significantly increased proliferation. LPA induced proliferation, regardless of ATX expression, and induced chemotaxis in all tested human leukemic cell lines and human CD34+ progenitors. LPC increased chemotaxis only in cells with high expression of endogenous ATX by at least 80%, demonstrating the autocrine action of ATX. Inhibition of ATX using a small molecule inhibitor selectively induced killing of ATX-expressing cell lines and reduced motility in these cells. Our data suggest that the production of bioactive LPA through ATX is involved in controlling proliferation and migration during hematopoiesis and that deregulation of ATX contributes to the pathogenesis of AML. (C) 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.