The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells.
The death-associated protein kinase 2 (DAPK2) belongs to a family of Ca(2+)/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/EBPepsilon, and lactoferrin. In summary, our findings implicate a role for DAPK2 in granulocyte maturation.
Rizzi
Mattia
M
Experimental Oncology/Hematology, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland.
Tschan
Mario P
MP
Britschgi
Christian
C
Britschgi
Adrian
A
Hügli
Barbara
B
Grob
Tobias J
TJ
Leupin
Nicolas
N
Mueller
Beatrice U
BU
Simon
Hans-Uwe
HU
Ziemiecki
Andrew
A
Torbett
Bruce E
BE
Fey
Martin F
MF
Tobler
Andreas
A
D000208:Acute Disease; D018952:Antigens, CD34 / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002908:Chronic Disease; D064550:Death-Associated Protein Kinases; D020869:Gene Expression Profiling; D006098:Granulocytes / Q000166:cytology / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D022423:Myeloid Cells / Q000166:cytology* / Q000502:physiology; D038042:Myelopoiesis / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology* / Q000502:physiology; D034741:RNA, Small Interfering / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D018952:Antigens, CD34; D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D034741:RNA, Small Interfering; D014212:Tretinoin; C579104:DAPK2 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases