@article{Lan Dan_Olga Klimenkova_Maxim Klimiankou_Jan-Henning Klusman_Marry M. van den Heuvel-Eibrink_Dirk Reinhardt_Karl Welte_Julia Skokowa_2012, place={Pavia, Italy}, title={The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells}, volume={97}, url={https://haematologica.org/article/view/6270}, DOI={10.3324/haematol.2011.055236}, abstractNote={<strong>Background</strong> Inhibitors of nicotinamide phosphoribosyltransferase have recently been validated as therapeutic targets in leukemia, but the mechanism of leukemogenic transformation downstream of this enzyme is unclear.<strong>Design and Methods</strong> Here, we evaluated whether nicotinamide phosphoribosyltransferase’s effects on aberrant proliferation and survival of myeloid leukemic cells are dependent on sirtuin and delineated the downstream signaling pathways operating during this process.<strong>Results</strong> We identified significant upregulation of sirtuin 2 and nicotinamide phosphoribosyltransferase levels in primary acute myeloid leukemia blasts compared to in hematopoietic progenitor cells from healthy individuals. Importantly, specific inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 significantly reduced proliferation and induced apoptosis in human acute myeloid leukemia cell lines and primary blasts. Intriguingly, we found that protein kinase B/AKT could be deacetylated by nicotinamide phosphoribosyltransferase and sirtuin 2. The anti-leukemic effects of the inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 were accompanied by acetylation of protein kinase B/AKT with subsequent inhibition by dephosphorylation. This leads to activation of glycogen synthase kinase-3 β via diminished phosphorylation and, ultimately, inactivation of β-catenin by phosphorylation.<strong>Conclusions</strong&gt; Our results provide strong evidence that nicotinamide phosphoribosyltransferase and sirtuin 2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the protein kinase B/AKT/ glycogen synthase kinase-3 β/β-catenin pathway is a target for inhibition of nicotinamide phosphoribosyltransferase or sirtuin 2 and, thereby, leukemia cell proliferation.}, number={4}, journal={Haematologica}, author={Lan Dan and Olga Klimenkova and Maxim Klimiankou and Jan-Henning Klusman and Marry M. van den Heuvel-Eibrink and Dirk Reinhardt and Karl Welte and Julia Skokowa}, year={2012}, month={Apr.}, pages={551-559} }