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Acute Leukemias

Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk

Leukemia volume 20, pages 2093–2101 (2006)Cite this article

Abstract

Acute myeloid leukemia (AML) cells express the cell surface antigen CD33 that, upon ligation with a monoclonal antibody (mAb), is a downregulator of cell growth in a Syk-dependent manner. An anti-CD33 mAb coupled to a toxin, gemtuzumab ozogamicin (GO), is used for the treatment of AML (Mylotarg). Therefore, we investigated whether the response of AML cells to GO treatment also depends on Syk expression. Forty primary AML samples (25 Syk-positive and 15 Syk-negative) were tested for their response to the anti-proliferative effects of GO and unmodified anti-CD33 mAb. A correlation between Syk expression and the response of leukemia cells to GO and anti-CD33 mAb was found. ‘Blocking’ of Syk by small interfering RNA resulted in unresponsiveness of AML cells to both GO and anti-CD33 mAb-mediated cytotoxicity. Syk upregulation by the de-methylating agent 5-azacytidine (5-aza) induced re-expression of Syk in some cases, resulting in enhanced GO and anti-CD33-mediated inhibition of leukemia cell growth. Thus, the cytotoxicity of both GO and anti-CD33 in primary AML samples was associated with Syk expression. 5-Aza restored Syk and increased the sensitivity of originally Syk-negative, non-responsive cells to CD33 ligation to levels of Syk-positive cells. These data have clinical significance for predicting response to GO and designing clinical trials.

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Acknowledgements

Larisa Balain designed and performed all of the experiments and prepared the paper. Edward D Ball co-designed the experiments and co-wrote the paper.

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  1. Blood and Marrow Transplantation Division, Department of Medicine and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA, USA

    L Balaian & E D Ball

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Correspondence to E D Ball.

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Balaian, L., Ball, E. Cytotoxic activity of gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia correlates with the expression of protein kinase Syk. Leukemia 20, 2093–2101 (2006). https://doi.org/10.1038/sj.leu.2404437

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