Bendall L J, Kortlepel K, Gottlieb D J
Department of Haematology, University of Sydney, Australia.
Exp Hematol. 1997 Feb;25(2):132-9.
Human acute myeloid leukemia (AML) cells adhere to bone marrow fibroblasts (BMF) and extracellular matrix proteins including fibronectin. Adhesion is increased when fibroblast monolayers are exposed to tumor necrosis factor-alpha (TNF) alone and in combination with interferon-gamma (IFN) or interleukin-4 (IL-4). The combination of TNF and IFN caused enhanced AML cell adhesion to treated BMFs, from a mean of 25.0 +/- 4.1% to 36.3 +/- 5.4% (p = 0.0007). Enhanced binding was partially a result of upregulated vascular cell adhesion molecule-1 expression on BMFs. Intercellular adhesion molecule-1 was also upregulated, but did not appear to play a role in the increased binding to cytokine-stimulated BMFs. In contrast to observed adhesion to resting BMFs, AML cells binding to TNF/IFN-stimulated BMFs rely more heavily on the VLA-4 alpha chain (CD49d). In some cases, alpha4 integrin chain antibody was more effective than beta1 antibody in blocking binding, suggesting that a non-beta1 alpha4 integrin, possibly alpha4 beta7, on AML cells may act as a stromal ligand. The addition of alpha4 antibody to beta1 and beta2 antibodies significantly increased the inhibition of AML cells to stimulated BMFs. The myeloid cytokines granulocyte colony stimulating factor, granulocyte-monocyte colony stimulating factor, interleukin-3 and stem cell factor enhanced the adhesion of AML blast cells to BMFs in some cases. The phorbol ester PMA, however, consistently upregulated AML cell-binding to BMFs, the increase being mediated entirely via beta1 and beta2 integrins without altering AML cell integrin expression. Binding of AML cells to marrow stroma can be enhanced by influences on leukemic cell or stroma. Enhanced binding under these conditions occurs via different pathways, illustrating the heterogeneity of mechanisms underlying leukemic cell retention within the bone marrow stroma.
人类急性髓系白血病（AML）细胞可黏附于骨髓成纤维细胞（BMF）以及包括纤连蛋白在内的细胞外基质蛋白。当成纤维细胞单层单独暴露于肿瘤坏死因子-α（TNF）以及与干扰素-γ（IFN）或白细胞介素-4（IL-4）联合作用时，黏附作用增强。TNF与IFN联合使用导致AML细胞与经处理的BMF的黏附增强，从平均25.0±4.1%增至36.3±5.4%（p = 0.0007）。黏附增强部分是由于BMF上血管细胞黏附分子-1表达上调。细胞间黏附分子-1也上调，但似乎在与细胞因子刺激的BMF结合增加中不起作用。与观察到的AML细胞与静止BMF的黏附不同，AML细胞与TNF/IFN刺激的BMF的结合更依赖于VLA-4α链（CD49d）。在某些情况下，α4整合素链抗体在阻断结合方面比β1抗体更有效，这表明AML细胞上一种非β1α4整合素，可能是α4β7，可能作为一种基质配体。将α4抗体与β1和β2抗体联合使用可显著增强对AML细胞与刺激的BMF结合的抑制作用。在某些情况下，髓系细胞因子粒细胞集落刺激因子、粒细胞-单核细胞集落刺激因子、白细胞介素-3和干细胞因子可增强AML原始细胞与BMF的黏附。然而，佛波酯PMA始终上调AML细胞与BMF的结合，这种增加完全通过β1和β2整合素介导，而不改变AML细胞整合素的表达。AML细胞与骨髓基质的结合可通过对白血病细胞或基质的影响而增强。在这些条件下增强的结合通过不同途径发生，这说明了白血病细胞保留在骨髓基质内的机制的异质性。
