CD34+/CD38- stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin
Open Access
- 11 October 2011
- journal article
- Published by Ferrata Storti Foundation (Haematologica) in Haematologica
- Vol. 97 (2), 219-226
- https://doi.org/10.3324/haematol.2010.035006
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. 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.Keywords
This publication has 38 references indexed in Scilit:
- Targeted therapy of chronic myeloid leukemiaBiochemical Pharmacology, 2010
- P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylateLeukemia, 2004
- Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacityLeukemia, 2003
- MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line modelsBlood, 2003
- Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid LeukemiaThe New England Journal of Medicine, 2003
- Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemiaCancer Cell, 2002
- Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or AmplificationScience, 2001
- Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First RelapseJournal of Clinical Oncology, 2001
- Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cellsBlood, 2001
- Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublinesLeukemia, 2000