Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia.
Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia.
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DOI：
10.1002/cam4.203
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发表时间：
2014-04
期刊：
影响因子：
4
通讯作者：
Sathyanarayana, Pradeep
中科院分区：
文献类型：
--
作者：
Favreau, Amanda J.;Vary, Calvin P. H.;Brooks, Peter C.;Sathyanarayana, Pradeep
以前，我们发现，盘状结构域受体1（DDR1），一类胶原激活的受体酪氨酸激酶（RTK）是高度上调骨髓（BM）衍生的CD33+白血病母细胞的急性髓细胞性白血病（AML）患者。由于DDR1是一类胶原激活的RTK，我们试图了解骨髓微环境中天然和重塑的IV型胶原的作用及其在白血病细胞中的功能意义。暴露于变性胶原IV显著增加K562细胞的迁移和粘附，这也导致增加DDR1和AKT的活化。此外，MMP 9的水平在变性胶原IV暴露的细胞的条件培养基（CM）中增加。质谱液相色谱/串联质谱QSTAR蛋白质组学分析揭示了在变性胶原IV CM中分泌颗粒蛋白3和InaD样蛋白的独家存在。重要的是，AML患者的BM样品与天然相比表现出增加的重塑胶原IV水平，如通过抗HUIV26抗体分析的。综上所述，我们第一次证明了重塑的IV型胶原蛋白是DDR1和AKT的有效激活剂，也可以调节髓系白血病细胞的迁移和粘附。此外，AML患者的BM中表达高水平的HUIV26隐蔽胶原IV表位。对这一现象的进一步理解可能会导致直接调节BM微环境和减弱白血病发生的治疗剂的开发。
Previously, we showed that discoidin domain receptor 1 (DDR1), a class of collagen-activated receptor tyrosine kinase (RTK) was highly upregulated on bone marrow (BM)-derived CD33+ leukemic blasts of acute myeloid leukemia (AML) patients. Herein as DDR1 is a class of collagen-activated RTK, we attempt to understand the role of native and remodeled collagen IV in BM microenvironment and its functional significance in leukemic cells. Exposure to denatured collagen IV significantly increased the migration and adhesion of K562 cells, which also resulted in increased activation of DDR1 and AKT. Further, levels of MMP9 were increased in conditioned media (CM) of denatured collagen IV exposed cells. Mass spectrometric liquid chromatography/tandem mass spectrometry QSTAR proteomic analysis revealed exclusive presence of Secretogranin 3 and InaD-like protein in the denatured collagen IV CM. Importantly, BM samples of AML patients exhibited increased levels of remodeled collagen IV compared to native as analyzed via anti-HUIV26 antibody. Taken together, for the first time, we demonstrate that remodeled collagen IV is a potent activator of DDR1 and AKT that also modulates both migration and adhesion of myeloid leukemia cells. Additionally, high levels of the HUIV26 cryptic collagen IV epitope are expressed in BM of AML patients. Further understanding of this phenomenon may lead to the development of therapeutic agents that directly modulate the BM microenvironment and attenuate leukemogenesis.
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