Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia
Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia
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DOI：
10.1182/blood-2007-12-124818
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发表时间：
2009-01-22
期刊：
影响因子：
20.3
通讯作者：
Appelbaum, Frederick R.
中科院分区：
文献类型：
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作者：
Becker, Pamela S.;Kopecky, Kenneth J.;Appelbaum, Frederick R.
骨髓微环境中急性髓系白血病 (AML) 母细胞的粘附可防止化疗诱导的细胞凋亡。原始细胞保留在骨髓内的一种机制是通过极晚期抗原 4 (VLA-4) 进行粘附，VLA-4 是与其主要配体、纤连蛋白和血管细胞粘附分子 1 (VCAM1) 结合的 α(4)β(1) 整合素异二聚体。为了检查 VLA-4 功能表达与 AML 预后的关系，我们研究了西南肿瘤组试验中接受蒽环类和阿糖胞苷诱导化疗的 175 名成人 AML 患者的骨髓样本。这些研究包括流式细胞术和配体结合和最大β(1)激活的功能性体外测定。 VLA-4 表达差异很大，α(4) 的平均表达率为 60.6%，并且与化疗反应、无复发或总生存 (OS) 没有显着相关。然而，通过 VLA-4 增加的可溶性 VCAM-1 结合与更长的 OS 显着相关（根据年龄进行校正）（P = .033）。 30 名可溶性 VCAM-1 结合大于或等于 40% 的患者的估计 5 年 OS 为 31%（95% 置信区间，14%-48%），而 72 名结合较低的患者的 5 年 OS 为 10%（置信区间，3%-17%）。因此，AML 母细胞的粘附和迁移特性似乎会影响化疗敏感性，因此可能是治疗靶点。 （血。2009；113：866-874）
Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow microenvironment confers protection from chemotherapy-induced apoptosis. One mechanism for retention of blasts within the bone marrow is adhesion via very late antigen-4 (VLA-4), the alpha(4)beta(1) integrin heterodimer that binds to its main ligands, fibronectin, and vascular cell adhesion molecule-1 (VCAM1). To examine the relationship of functional expression of VLA-4 to prognosis in AML, we studied marrow samples from 175 adult AML patients who underwent induction chemotherapy with anthracycline and cytarabine on Southwest Oncology Group trials. The studies included flow cytometry and functional in vitro assays for ligand binding and maximal beta(1) activation. VLA-4 expression varied widely, with mean expression 60.6% for alpha(4), and was not significantly associated with response to chemotherapy, relapse-free, or overall survival (OS). However, increased binding of soluble VCAM- 1 via VLA-4 was significantly associated with longer OS, corrected for age (P = .033). Estimated 5-year OS was 31% (95% confidence interval, 14%-48%) in 30 patients with soluble VCAM-1 binding greater than or equal to 40%, compared with 10% (confidence interval, 3%-17%) in 72 patients with lower binding. Adhesion and migratory properties of AML blasts thus appear to influence chemosensitivity and therefore may be therapeutic targets. (Blood. 2009;113:866-874)