Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as ...the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis ...levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin IL-2 production, and interferon-gamma and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9; and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon-gamma and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiproliferative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.
The Gambia is a small and economically weak nation state in West Africa. Due to the fact that the Gambia is not endowed with precious natural resources such as oil, gas, platinum and gold, it is ...generally not found in the geo-strategic calculations of the big powers such as France, Britain and China. Consequently, the political and socioeconomic affairs of the Gambia do not get adequate scholarly attention unless it is an ugly story about military coups. The situation is worsened by the reality of an undeveloped culture of research in the Gambia, which is reflected by the presence of just one public university. Against this backdrop, this paper sought to fill this void by unpacking the challenges and opportunities of the Gambia‘s membership of the African Union (AU). This aim was achieved by relying on document study and interdisciplinary discourse analysis in its broadest form. This paper argues that there are a lot of opportunities than challenges with the Gambia‘s belonging to the AU. In order to fully understand this situation, it is proposed that any study about this should be located within the historical and broader context. To appreciate an avalanche of benefits in the membership of the AU, one needs to be also familiar with the AU‘s challenges in its quest to achieve its set goals.
Correction to: Leukemia; doi:10.1038/leu.2012.119; advance online publication, 3 May 2012 Since the publication of this article, the authors have noticed an error in Figure 4a, specifically that the ...structures of the methyl-pomalidomide enantiomers were missing a carbonyl group. The error has now been rectified, and the correct article (with the correct figure 4) appears in this issue.
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