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The protein kinase C agonist PEP005 increases NF‐κB expression, induces differentiation and increases constitutive chemokine release by primary acute myeloid leukaemia cells
Author(s) -
Olsnes Astrid Marta,
Ersvær Elisabeth,
Ryningen Anita,
Paulsen Kristin,
Hampson Peter,
Lord Janet M.,
Gjertsen Bjørn Tore,
Kristoffersen Einar Klæboe,
Bruserud Øystein
Publication year - 2009
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2009.07691.x
Subject(s) - chemokine , ccl5 , cxcl2 , ccl7 , ccl3 , cancer research , microbiology and biotechnology , biology , cxc chemokine receptors , chemistry , chemokine receptor , immunology , ccl2 , t cell , inflammation , immune system , il 2 receptor
Summary Acute myeloid leukaemia (AML) cells show constitutive release of several chemokines that occurs in three major clusters: (I) chemokine (C‐C motif) ligand (CCL)2–4/chemokine (C‐X‐C motif) ligand (CXCL)1/8, (II) CCL5/CXCL9–11 and (III) CCL13/17/22/24/CXCL5. Ingenol‐3‐angelate (PEP005) is an activator of protein kinase C and has antileukaemic and immunostimulatory effects in AML. We investigated primary AML cells derived from 35 unselected patients and determined that PEP005 caused a dose‐dependent increase in the release of chemokines from clusters I and II, including several T cell chemotactic chemokines. The release of granulocyte‐macrophage colony‐stimulating factor and hepatocyte growth factor was also increased. CCL2–4/CXCL1/8 release correlated with nuclear factor (NF)‐κB expression in untreated AML cells, and PEP005‐induced chemokine production was associated with further increases in the expression of the NF‐κB subunits p50, p52 and p65. Increased DNA binding of NF‐κB was observed during exposure to PEP005, and the specific NF‐κB inhibitor BMS‐345541 reduced constitutive chemokine release even in the presence of PEP005. Finally, PEP005 decreased expression of stem cell markers (CD117, CXCR4) and increased lineage‐associated CD11b and CD14 expression. To conclude, PEP005 has a unique functional pharmacological profile in human AML. Previous studies have described proapoptotic and T cell stimulatory effects and the present study describes additional T cell chemotactic and differentiation‐inducing effects.