fk-866 and Waldenstrom-Macroglobulinemia

Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD. We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo RESULTS: We found that Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD. Our results show intracellular NAD

Topics: Acrylamides; Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; B-Lymphocytes; Caspase 3; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Humans; Mice; Mice, SCID; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Myeloid Differentiation Factor 88; NF-kappa B; Nicotinamide Phosphoribosyltransferase; Piperidines; Poly(ADP-ribose) Polymerases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Receptors, CXCR4; Signal Transduction; Waldenstrom Macroglobulinemia