CD52 is a molecular target in advanced systemic mastocytosis.
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.
Department of Laboratory Medicine, matthias.mayerhofer@meduniwien.ac.at.
Gregor
G
Hoermann
Department of Internal Medicine I, Division of Hematology and Hemostaseology.
Katharina
K
Blatt
Department of Laboratory Medicine.
Georg
G
Greiner
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria;
Eva Maria
EM
Putz
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria;
Angelika
A
Berger
Ludwig Boltzmann Cluster Oncology, Vienna, Austria;
Harald
H
Herrmann
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Ludwig Boltzmann Cluster Oncology, Vienna, Austria;
Sabine
S
Cerny-Reiterer
Department of Internal Medicine I, Division of Hematology and Hemostaseology.
Karoline V
KV
Gleixner
Institute of Pathology, Ludwig Maximilians University Munich, Munich, Germany;
Christoph
C
Walz
Department of Surgery, Division of Thoracic Surgery, and.
Konrad
K
Hoetzenecker
Department of Pathology, Medical University of Vienna, Vienna, Austria;
Leonhard
L
Müllauer
Medizinische Universitätsklinik, Universitätsmedizin Mannheim, Mannheim, Germany; and.
Andreas
A
Reiter
Institute of Pathology, Ludwig Maximilians University Munich, Munich, Germany;
Karl
K
Sotlar
Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria;
Veronika
V
Sexl
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Ludwig Boltzmann Cluster Oncology, Vienna, Austria;
Peter
P
Valent
Ludwig Boltzmann Institute of Osteology, Hanusch Hospital, Vienna, Austria matthias.mayerhofer@meduniwien.ac.at.
Matthias
M
Mayerhofer
D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis* / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis* / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000074301:CD52 Antigen; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000502:physiology; D011905:Genes, ras; D006023:Glycoproteins / Q000032:analysis* / Q000276:immunology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000502:physiology
D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; C000613863:Cd52 protein, mouse; D006023:Glycoproteins; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000074323:Alemtuzumab; D019009:Proto-Oncogene Proteins c-kit; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
CAMPATH-1; RAS G12V; alemtuzumab; mast cell leukemia