C-type lectin-like molecule-1: A novel myeloid cell surface marker associated with acute myeloid leukemia
C-type lectin-like molecule-1: A novel myeloid cell surface marker associated with acute myeloid leukemia
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DOI：
10.1158/0008-5472.can-04-1659
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发表时间：
2004-11-15
期刊：
影响因子：
11.2
通讯作者：
Kiuisbeek, AM
中科院分区：
文献类型：
--
作者：
Bakker, ABH;van den Oudenrijn, S;Kiuisbeek, AM
急性髓性白血病（AML）由于治疗抵抗性复发而预后不良。人源化抗CD 33抗体（Mylotarg）在复发性AML中显示出有限的缓解率。为了发现新的AML抗体靶标，我们使用噬菌体展示技术结合流式细胞术对AML肿瘤样品选择了一组单链Fv片段。一个选择的单链Fv片段广泛地与AML样品和外周血中的髓样细胞谱系反应。表达克隆鉴定了被识别为C型凝集素样分子-1（CLL-1）的抗原，这是一种以前未描述的跨膜糖蛋白。用由单链Fv片段产生的人抗CLL-1抗体分析CLL-1表达。CLL-1限于造血谱系，特别是存在于外周血和骨髓中的骨髓细胞。CLL-1在未定型的CD 34（+）/CD 38（-）或CD 34（+）/CD 33（-）干细胞上不存在，而存在于CD 34（+）/CD 38（+）或CD 34（+）/CD 33（+）祖细胞的亚群上。CLL-1在其他组织中不表达。相比之下，对原发性AML的分析表明，CLL-1在92%（74例中的68例）的样本中表达。作为AML标志物，CLL-1能够与CD 33互补，因为67%（12例中的8例）的CD 33（-）AML表达CLL-1。CLL-1在慢性粒细胞白血病和骨髓增生异常综合征的CD 34（+）细胞中表达变化（10-60%），但在13例急性淋巴细胞白血病中有12例缺失。AML反应性与正常细胞上的受限表达相结合，将CLL-1鉴定为AML治疗的新的潜在靶标。
Acute myeloid leukemia (AML) has a poor prognosis due to treatment-resistant relapses. A humanized anti-CD33 antibody (Mylotarg) showed a limited response rate in relapsed AML. To discover novel AML antibody targets, we selected a panel of single chain Fv fragments using phage display technology combined with flow cytometry on AML tumor samples. One selected single chain Fv fragment broadly reacted with AML samples and with myeloid cell lineages within peripheral blood. Expression cloning identified the antigen recognized as C-type lectin-like molecule-1 (CLL-1), a previously undescribed transmembrane glycoprotein. CLL-1 expression was analyzed with a human anti-CLL-1 antibody that was generated from the single chain Fv fragment. CLL-1 is restricted to the hematopoietic lineage, in particular to myeloid cells present in peripheral blood and bone marrow. CLL-1 is absent on uncommitted CD34(+)/ CD38(-) or CD34(+)/CD33(-) stem cells and present on subsets of CD34(+)/ CD38(+) or CD34(+)/CD33(+) progenitor cells. CLL-1 is not expressed in any other tissue. In contrast, analysis of primary AMLs demonstrated CLL-1 expression in 92% (68 of 74) of the samples. As an AML marker, CLL-1 was able to complement CD33, because 67% (8 of 12) of the CD33(-) AMLs expressed CLL-1. CLL-1 showed variable expression (10-60%) in CD34(+) cells in chronic myelogenous leukemia and myelodysplastic syndrome but was absent in 12 of 13 cases of acute lymphoblastic leukemia. The AML reactivity combined with the restricted expression on normal cells identifies CLL-1 as a novel potential target for AML treatment.