Published online before print March 8, 2007

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(Journal of Leukocyte Biology. 2007;81:1599-1608.)
© 2007 by Society for Leukocyte Biology

The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells

Mattia Rizzi^*, Mario P. Tschan^*,1, Christian Britschgi^*, Adrian Britschgi^*, Barbara Hügli^*, Tobias J. Grob^*, Nicolas Leupin^*, Beatrice U. Mueller, Hans-Uwe Simon, Andrew Ziemiecki, Bruce E. Torbett^||, Martin F. Fey^¶ and Andreas Tobler^**

^* Experimental Oncology/Hematology,
^¶ Medical Oncology, and
^** Hematology, Inselspital, and
The Tiefenau Laboratories, Department of Clinical Research, and Departments of
Internal Medicine and
Pharmacology, University of Bern, Bern, Switzerland; and
^|| Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA

¹ Correspondence: Experimental Oncology/Hematology, Inselspital and Department of Clinical Research, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland. E-mail: mtschan@dkf.unibe.ch

The death-associated protein kinase 2 (DAPK2) belongs to a family of Ca²⁺/calmodulin-regulated serine/threonine kinases involved in apoptosis. During investigation of candidate genes operative in granulopoiesis, we identified DAPK2 as highly expressed. Subsequent investigations demonstrated particularly high DAPK2 expression in normal granulocytes compared with monocytes/macrophages and CD34⁺ progenitor cells. Moreover, significantly increased DAPK2 mRNA levels were seen when cord blood CD34⁺ cells were induced to differentiate toward neutrophils in tissue culture. In addition, all-trans retinoic acid (ATRA)-induced neutrophil differentiation of two leukemic cell lines, NB4 and U937, revealed significantly higher DAPK2 mRNA expression paralleled by protein induction. In contrast, during differentiation of CD34⁺ and U937 cells toward monocytes/macrophages, DAPK2 mRNA levels remained low. In primary leukemia, low expression of DAPK2 was seen in acute myeloid leukemia samples, whereas chronic myeloid leukemia samples in chronic phase showed intermediate expression levels. Lentiviral vector-mediated expression of DAPK2 in NB4 cells enhanced, whereas small interfering RNA-mediated DAPK2 knockdown reduced ATRA-induced granulocytic differentiation, as evidenced by morphology and neutrophil stage-specific maturation genes, such as CD11b, G-CSF receptor, C/EBP, and lactoferrin. In summary, our findings implicate a role for DAPK2 in granulocyte maturation.

Key Words: DAPK2 • DRP-1 • AML • myelopoiesis

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