Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias
Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias
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DOI：
10.1182/blood-2004-07-2585
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发表时间：
2005-05-01
期刊：
影响因子：
20.3
通讯作者：
Wodnar-Filipowicz, A
中科院分区：
文献类型：
--
作者：
Nowbakht, P;Ionescu, MCS;Wodnar-Filipowicz, A
自然杀伤(NK)细胞介导的抗肿瘤细胞杀伤活性需要肿瘤相关配体参与激活NK受体。在这里，我们研究了NKG2D和天然细胞毒性受体(NCRs)在识别人类白血病中的作用。为了检测NCRs识别的未知细胞表面分子，我们开发了NKp30、NKp44和NKp46的可溶性形式作为与假定的同源配体结合的染色试剂。对健康造血细胞中NKG2D的UL16结合蛋白-1(ULBP1)、ULBP2和ULBP3配体以及NKp30、NKp44和NKp46的潜在配体的分析表明，骨髓来源的CD34+祖细胞具有配体阴性表型，并在髓系分化过程中获得了细胞表面配体。在急性髓系白血病(AML)中，大约80%的患者的白血病原始细胞表达极低水平的ULBPs和NCR特异性配体。促进分化的髓系生长因子与干扰素-γ一起治疗，上调了AML原始细胞表面ULBP1和可能的NCR配体的水平，从而增加了对NK细胞介导的裂解的敏感性。我们的结论是，AML的配体阴性/低表型是恶性转化过程中细胞成熟停滞的结果，激活NKG2D和NCR受体的配体表达缺陷可能会影响NK细胞对白血病的识别。
Natural killer (NK) cell-mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKP46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow-derived CD34+ progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-gamma, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell-mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.