title: CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin.
abstract: BACKGROUND
  CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias.
  
  
  METHODS
  We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined.
  
  
  RESULTS
  As assessed by flow cytometry, stem cell-enriched CD34(+)/CD38(-)/CD123(+) leukemic cells expressed significantly higher levels of CD33 compared to normal CD34(+)/CD38(-) stem cells. Moreover, highly enriched leukemic CD34(+)/CD38(-) cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34(+)/CD38(-) cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells.
  
  
  CONCLUSIONS
  CD33 is expressed abundantly on immature CD34(+)/CD38(-) stem cells and may serve as a stem cell target in chronic myeloid leukemia.
authors: Ludwig Boltzmann Cluster Oncology, Vienna, Austria.
authors: Harald
authors: H
authors: Herrmann
authors: Sabine
authors: S
authors: Cerny-Reiterer
authors: Karoline V
authors: KV
authors: Gleixner
authors: Katharina
authors: K
authors: Blatt
authors: Susanne
authors: S
authors: Herndlhofer
authors: Werner
authors: W
authors: Rabitsch
authors: Eva
authors: E
authors: Jäger
authors: Gerlinde
authors: G
authors: Mitterbauer-Hohendanner
authors: Berthold
authors: B
authors: Streubel
authors: Edgar
authors: E
authors: Selzer
authors: Ilse
authors: I
authors: Schwarzinger
authors: Wolfgang R
authors: WR
authors: Sperr
authors: Peter
authors: P
authors: Valent
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000617:Aminoglycosides / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D015703:Antigens, CD / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000079982:Gemtuzumab; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063268:Sialic Acid Binding Ig-like Lectin 3; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D000079982:Gemtuzumab; D051997:ADP-ribosyl Cyclase 1