Correlation of tumoricidal activity of lenalidomide against hematologic tumor cells with cyclin D1/D2 expression and effect on tumor-suppressor gene upregulation.

Abstract

8090 Background: Lenalidomide (len) treatment leads to cell cycle arrest and apoptosis in some but not all multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Len treatment of sensitive cells appears to up-regulate tumor suppressor gene expression. We sought to define the role of baseline and len-induced expression of cyclin D family members and tumor suppressor genes in mantle cell lymphoma (MCL) and MM cell lines with the aim of identifying correlates to len-induced anti-proliferative activity. Methods: Anti-proliferative activity was assessed in a panel of 10 MM and 14 NHL cell lines as well primary cells derived from 3 MM and 2 MCL patients. Anti-proliferative activity (at 72 hrs) was correlated with baseline and len-induced expression of cyclins D1-3 and multiple tumor suppressor genes measured by RT-PCR. The effect of len on the nuclear localization of p27 protein was also assessed. Results: In MM and MCL cells sensitivity to len-mediated anti-proliferative activity appeared to correlate with baseline expression of cyclin D1 (p<.01, MM; p<.05, MCL) and p16INK4A (MCL p<.05), and inversely correlate with cyclin D2 expression (p<.05, MM, MCL); no relationship with cyclin D3 expression was seen. Cyclin D1/D2 results were similar in primary MM and MCL cells. Anti-proliferative activity also correlated with len-mediated upregulation of tumor suppressor genes, p15INK4B (<.005), p16INK4A(<.01), p18INK4C(<.01), p19INK4D(<.01) and p27kip 1(<.05) and secreted protein acidic and rich in cysteine (SPARC; <.01) in MM cells, and p27kip1(<.05) and SPARC (<.01) in MCL cells. Len-treated H929 cells had a ∼2-fold increase in nuclear versus cytosolic localization of p27. Conclusions: In MM and MCL cells, len-mediated anti-proliferative activity correlates with constitutively over-expressed cyclin D1, but appears inactive in cells over-expressing cyclin D2. Len-mediated anti-proliferative activity also appears to associate with upregulation of distinct tumor suppressor genes. Identifying potential markers of len-mediated activity provides further insight into mechanisms likely to be involved in its clinical activity in B cell malignancies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene