Hoermann Gregor, Blatt Katharina, Greiner Georg, Putz Eva Maria, Berger Angelika, Herrmann Harald, Cerny-Reiterer Sabine, Gleixner Karoline V, Walz Christoph, Hoetzenecker Konrad, Müllauer Leonhard, Reiter Andreas, Sotlar Karl, Sexl Veronika, Valent Peter, Mayerhofer Matthias
Department of Laboratory Medicine,
Department of Internal Medicine I, Division of Hematology and Hemostaseology.
FASEB J. 2014 Aug;28(8):3540-51. doi: 10.1096/fj.14-250894. Epub 2014 Apr 23.
Advanced systemic mastocytosis (SM) is an aggressive hematopoietic neoplasm with poor prognosis and short survival times. So far, no curative therapy is available for affected patients. We have identified the cell surface antigen CD52 (CAMPATH-1) as a molecular target expressed abundantly on the surface of primary neoplastic mast cells (MCs) in patients with advanced SM. In contrast, neoplastic MCs of patients with indolent SM and normal MCs expressed only low levels or did not express CD52. To study the mechanisms of CD52 expression and the value of this antigen as a potential therapeutic target, we generated a human MC cell line, designated MCPV-1, by lentiviral immortalization of cord blood-derived MC progenitor cells. Functional studies revealed that activated RAS profoundly promotes surface expression of CD52. The CD52-targeting antibody alemtuzumab induced cell death in CD52(+) primary neoplastic MCs obtained from patients with SM as well as in MCPV-1 cells. NSG mice xenotransplanted with MCPV-1 cells survived significantly longer after treatment with alemtuzumab (median survival: 31 d untreated vs. 46 d treated; P=0.0012). We conclude that CD52 is a novel marker and potential therapeutic target in neoplastic MCs in patients with advanced SM.
晚期系统性肥大细胞增多症（SM）是一种侵袭性造血肿瘤，预后不良且生存时间短。到目前为止，尚无针对受影响患者的治愈性疗法。我们已确定细胞表面抗原CD52（CAMPATH-1）是晚期SM患者原发性肿瘤性肥大细胞（MC）表面大量表达的分子靶点。相比之下，惰性SM患者的肿瘤性MC和正常MC仅表达低水平或不表达CD52。为了研究CD52表达的机制以及该抗原作为潜在治疗靶点的价值，我们通过慢病毒永生化脐血来源的MC祖细胞，建立了一种人MC细胞系，命名为MCPV-1。功能研究表明，活化的RAS可显著促进CD52的表面表达。靶向CD52的抗体阿仑单抗可诱导从SM患者获得的CD52(+)原发性肿瘤性MC以及MCPV-1细胞死亡。用阿仑单抗治疗后，移植了MCPV-1细胞的NSG小鼠存活时间显著延长（中位生存期：未治疗组为31天，治疗组为46天；P=0.0012）。我们得出结论，CD52是晚期SM患者肿瘤性MC中的一种新型标志物和潜在治疗靶点。
