title: Identification of campath-1 (CD52) as novel drug target in neoplastic stem cells in 5q-patients with MDS and AML.
abstract: OBJECTIVE
  The CD52-targeted antibody alemtuzumab induces major clinical responses in a group of patients with myelodysplastic syndromes (MDS). The mechanism underlying this drug effect remains unknown.
  
  
  METHODS
  We asked whether neoplastic stem cells (NSC) in patients with MDS (n = 29) or acute myelogenous leukemia (AML; n = 62) express CD52.
  
  
  RESULTS
  As assessed by flow cytometry, CD52 was found to be expressed on NSC-enriched CD34(+)/CD38(-) cells in 8/11 patients with MDS and isolated del(5q). In most other patients with MDS, CD52 was weakly expressed or not detectable on NSC. In AML, CD34(+)/CD38(-) cells displayed CD52 in 23/62 patients, including four with complex karyotype and del(5q) and one with del(5q) and t(1;17;X). In quantitative PCR (qPCR) analyses, purified NSC obtained from del(5q) patients expressed CD52 mRNA. We were also able to show that CD52 mRNA levels correlate with EVI1 expression and that NRAS induces the expression of CD52 in AML cells. The CD52-targeting drug alemtuzumab, was found to induce complement-dependent lysis of CD34(+)/CD38(-)/CD52(+) NSC, but did not induce lysis in CD52(-) NSC. Alemtuzumab also suppressed engraftment of CD52(+) NSC in NSG mice. Finally, CD52 expression on NSC was found to correlate with a poor survival in patients with MDS and AML.
  
  
  CONCLUSIONS
  The cell surface target Campath-1 (CD52) is expressed on NSC in a group of patients with MDS and AML. CD52 is a novel prognostic NSC marker and a potential NSC target in a subset of patients with MDS and AML, which may have clinical implications and may explain clinical effects produced by alemtuzumab in these patients.
authors.affiliation: Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria;
authors.forename: Katharina
authors.initials: K
authors.lastname: Blatt
authors.affiliation: Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Austria;
authors.forename: Gregor
authors.initials: G
authors.lastname: Hoermann
authors.affiliation: Department for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Austria;
authors.forename: Michael
authors.initials: M
authors.lastname: Willmann
authors.affiliation: Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria;
authors.forename: Irina
authors.initials: I
authors.lastname: Sadovnik
authors.affiliation: Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria;
authors.forename: Susanne
authors.initials: S
authors.lastname: Herndlhofer
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Vienna, Austria;
authors.forename: Berthold
authors.initials: B
authors.lastname: Streubel
authors.affiliation: Department of Internal Medicine I, Bone Marrow Transplantation Unit, Medical University of Vienna, Austria;
authors.forename: Werner
authors.initials: W
authors.lastname: Rabitsch
authors.affiliation: Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria;
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.affiliation: Ludwig Boltzmann Institute of Osteology, Hanusch-Hospital, Vienna, Austria; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mayerhofer
authors.affiliation: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Authors' Affiliations: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria; peter.valent@meduniwien.ac.at.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D000074301:CD52 Antigen; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D011905:Genes, ras; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D023041:Xenograft Model Antitumor Assays
chemical_list: 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; D000074323:Alemtuzumab