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. DESIGN AND 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.
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. DESIGN AND 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 leukemicCD34(+)/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 leukemicCD34(+)/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: E L Sievers; R A Larson; E A Stadtmauer; E Estey; B Löwenberg; H Dombret; C Karanes; M Theobald; J M Bennett; M L Sherman; M S Berger; C B Eten; M R Loken; J J van Dongen; I D Bernstein; F R Appelbaum Journal: J Clin Oncol Date: 2001-07-01 Impact factor: 44.544
Authors: K Naito; A Takeshita; K Shigeno; S Nakamura; S Fujisawa; K Shinjo; H Yoshida; K Ohnishi; M Mori; S Terakawa; R Ohno Journal: Leukemia Date: 2000-08 Impact factor: 11.528
Authors: V H van Der Velden; J G te Marvelde; P G Hoogeveen; I D Bernstein; A B Houtsmuller; M S Berger; J J van Dongen Journal: Blood Date: 2001-05-15 Impact factor: 22.113
Authors: Neil P Shah; John M Nicoll; Bhushan Nagar; Mercedes E Gorre; Ronald L Paquette; John Kuriyan; Charles L Sawyers Journal: Cancer Cell Date: 2002-08 Impact factor: 31.743
Authors: T Illmer; M Schaich; U Platzbecker; J Freiberg-Richter; U Oelschlägel; M von Bonin; S Pursche; T Bergemann; G Ehninger; E Schleyer Journal: Leukemia Date: 2004-03 Impact factor: 11.528
Authors: Stephen G O'Brien; François Guilhot; Richard A Larson; Insa Gathmann; Michele Baccarani; Francisco Cervantes; Jan J Cornelissen; Thomas Fischer; Andreas Hochhaus; Timothy Hughes; Klaus Lechner; Johan L Nielsen; Philippe Rousselot; Josy Reiffers; Giuseppe Saglio; John Shepherd; Bengt Simonsson; Alois Gratwohl; John M Goldman; Hagop Kantarjian; Kerry Taylor; Gregor Verhoef; Ann E Bolton; Renaud Capdeville; Brian J Druker Journal: N Engl J Med Date: 2003-03-13 Impact factor: 91.245
Authors: I Jedema; R M Y Barge; V H J van der Velden; B A Nijmeijer; J J M van Dongen; R Willemze; J H F Falkenburg Journal: Leukemia Date: 2004-02 Impact factor: 11.528
Authors: Rebecca Warfvinge; Linda Geironson; Mikael N E Sommarin; Stefan Lang; Christine Karlsson; Teona Roschupkina; Leif Stenke; Jesper Stentoft; Ulla Olsson-Strömberg; Henrik Hjorth-Hansen; Satu Mustjoki; Shamit Soneji; Johan Richter; Göran Karlsson Journal: Blood Date: 2017-01-25 Impact factor: 22.113
Authors: Harald Herrmann; Irina Sadovnik; Gregor Eisenwort; Thomas Rülicke; Katharina Blatt; Susanne Herndlhofer; Michael Willmann; Gabriele Stefanzl; Sigrid Baumgartner; Georg Greiner; Axel Schulenburg; Niklas Mueller; Werner Rabitsch; Martin Bilban; Gregor Hoermann; Berthold Streubel; Daniel A Vallera; Wolfgang R Sperr; Peter Valent Journal: Blood Adv Date: 2020-10-27
Authors: Peter Valent; Irina Sadovnik; Gregor Eisenwort; Harald Herrmann; Karin Bauer; Niklas Mueller; Wolfgang R Sperr; Daniel Wicklein; Udo Schumacher Journal: Semin Cancer Biol Date: 2019-08-10 Impact factor: 15.707
Authors: Irina Sadovnik; Harald Herrmann; Gregor Eisenwort; Katharina Blatt; Gregor Hoermann; Niklas Mueller; Wolfgang R Sperr; Peter Valent Journal: Exp Hematol Date: 2017-04-27 Impact factor: 3.084
Authors: Axel Schulenburg; Katharina Blatt; Sabine Cerny-Reiterer; Irina Sadovnik; Harald Herrmann; Brigitte Marian; Thomas W Grunt; Christoph C Zielinski; Peter Valent Journal: J Hematol Oncol Date: 2015-02-25 Impact factor: 17.388
Authors: Sabine Cerny-Reiterer; Renata A Meyer; Harald Herrmann; Barbara Peter; Karoline V Gleixner; Gabriele Stefanzl; Emir Hadzijusufovic; Winfried F Pickl; Wolfgang R Sperr; Junia V Melo; Hiroshi Maeda; Ulrich Jäger; Peter Valent Journal: Oncotarget Date: 2014-03-15
Authors: Irina Sadovnik; Andrea Hoelbl-Kovacic; Harald Herrmann; Gregor Eisenwort; Sabine Cerny-Reiterer; Wolfgang Warsch; Gregor Hoermann; Georg Greiner; Katharina Blatt; Barbara Peter; Gabriele Stefanzl; Daniela Berger; Martin Bilban; Susanne Herndlhofer; Heinz Sill; Wolfgang R Sperr; Berthold Streubel; Christine Mannhalter; Tessa L Holyoake; Veronika Sexl; Peter Valent Journal: Clin Cancer Res Date: 2015-11-25 Impact factor: 12.531