Myeloid precursors and acute myeloid leukemia cells express multiple CD33-related Siglecs
Myeloid precursors and acute myeloid leukemia cells express multiple CD33-related Siglecs
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DOI：
10.1016/j.exphem.2006.03.003
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发表时间：
2006-06-01
影响因子：
2.6
通讯作者：
Varki, Ajit
中科院分区：
文献类型：
--
作者：
Nguyen, Dzung H.;Ball, Edward D.;Varki, Ajit
目标。CD33是骨髓单核细胞前体细胞和循环单核细胞的细胞表面标志，也存在于急性髓系白血病(AML)细胞上。CD33属于唾液酸结合的细胞表面蛋白家族Siglecs，其中还有7个功能与CD33相关的Siglecs(CD33rSiglecs)。我们试图鉴定其他CD33rSiglecs在骨髓前体细胞和AML细胞上的表达谱，并询问它们是否有可能作为治疗的靶点。用流式细胞仪分析细胞表面CD33rSiglecs。比较了某些抗Siglec抗体对毒素介导的Siglec表达细胞株的靶向杀伤能力。我们证明Siglecs-3、-5、-6、-7和-9在正常骨髓前体细胞亚群上表达，包括原单核细胞和髓细胞。此外，大多数AML(但不是所有)细胞都表达这些Siglecs。Siglec的类型和表达水平在不同病例之间有很大的差异，每个病例都有唯一的CD33rSiglec指纹。单独的抗Siglec抗体和Saporin毒素结合的二次抗体可以靶向导致粒单核细胞白血病细胞死亡，而靶向多个Siglec抗体可以提高细胞杀伤率。靶细胞的唾液酸酶处理进一步增强了细胞毒性，从而改善了抗体结合。我们还证实了抗体结合诱导Siglecs从细胞表面快速内化，这是通过皂苷杀死细胞的必要条件。多个CD33rSiglecs在正常和恶性骨髓瘤细胞上表达。以这些Siglecs为靶点，可能联合使用，可以改善抗CD33抗体治疗，或用作抗CD33抗体的替代品。(C)2006年国际实验血液学学会。由爱思唯尔公司出版。
Objectives. CD33 is a cell surface marker of committed myelomonocytic precursors and circulating monocytes, and is also found on acute myeloid leukemia (AML) cells. CD33 belongs to a family of sialic acid-binding cell surface proteins named Siglecs, among which there are 7 other functional CD33-related Siglecs (CD33rSiglecs). We sought to characterize the spectrum of expression of the other CD33rSiglecs on bone marrow precursors and AML cells and asked if they can potentially serve as targets for therapy.Methods. Cell surface CD33rSiglecs were analyzed by How cytometry. The ability of certain anti-Siglec antibodies to target toxin-mediated cell killing of Siglec-expressing cell lines was characterized and compared.Results. We demonstrate that Siglecs-3, -5, -6, -7, and -9 are expressed on subsets of normal bone marrow precursors, including promonocytes and myelocytes. Furthermore, most AML (but not ALL) cells express these Siglecs. There is substantial variability in Siglec type and expression level between cases, with each having a unique '' CD33rSiglec fingerprint.'' Individual anti-Siglec antibodies along with a saporin toxin-conjugated secondary antibody can target myelomonocytic leukemia cells for death, and targeting of multiple Siglecs improves cell killing. Cytotoxicity was further enhanced by sialidase treatment of target cells, which improves antibody binding. We also confirmed that antibody binding induced rapid internalization of Siglecs from the cell surface, which is a requirement for cell killing via saporin.Conclusions. Multiple CD33rSiglecs are expressed on normal and malignant myelomonoyctic cells. Targeting these Siglecs, possibly in combinations, could improve anti-CD33 antibody therapy or be used as an alternative to anti-CD33. (c) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.