Abstract
Thalidomide, lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma. However, their effects on plasma cells, the healthy counterpart of myeloma cells, are unknown. Here, we investigated lenalidomide effects on normal human plasma cell generation using an in vitro model. Lenalidomide inhibited the generation of pre-plasmablasts and early plasma cells, while it moderately affected plasmablast production. It also reduced the expression level of Ikaros, Aiolos, and IRF4 transcription factors, in plasmablasts and early plasma cells. This suggests that their differential sensitivity to lenalidomide is not due to a difference in Ikaros or Aiolos degradation. Lenalidomide also inhibited long-lived plasma cell generation, but did not impair their long-term survival once generated. This last observation is in agreement with the finding that lenalidomide treatment for 3-18 months did not affect the bone marrow healthy plasma cell count in allografted patients with multiple myeloma. Our findings should prompt to investigate whether lenalidomide resistance in patients with multiple myeloma could be associated with the emergence of malignant plasmablasts or long-lived plasma cells that are less sensitive to lenalidomide.
Highlights
Thalidomide and its immunomodulatory derivatives (IMiDs®) lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma (MM), a malignant plasma cell (PC) disorder [1,2,3]
To investigate the effect of lenalidomide on the generation of human long-lived PCs (LLPCs) from memory B cells (MBCs), we used an in vitro model that mimics the various steps associated with this process in lymph nodes, blood and bone marrow (BM) [19, 20, 22]
In step 2, cells are cultured with IL-2, IL-10, IL-15 and IL-6, but without CD40 ligand (CD40L) and ODN for three days to promote differentiation into CD20-CD38+ Pacific BlueTM (PB), which start to differentiate into poorly proliferating CD20CD38+CD138+ early PCs
Summary
Thalidomide and its immunomodulatory derivatives (IMiDs®) lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma (MM), a malignant plasma cell (PC) disorder [1,2,3]. IMiDs directly kill multiple myeloma cells (MMCs) and target the tumor environment by stimulating T cell function and inhibiting angiogenesis and tumor necrosis factor production by monocytes [4] These activities are mediated through IMiD ability to promote binding of the Ikaros and Aiolos transcription factors to cereblon (CRBN), which forms an E3 ubiquitin ligase complex together with damaged DNA binding 1 (DDB1), cullin-4A (CUL4A) and regulator of cullins 1 (ROC1) [5, 6]. This results in the activation of CRBN E3 ligase activity, leading to Ikaros and Aiolos ubiquitination and proteasomal degradation [7,8,9]. Recent works have shown that lenalidomide-induced IRF4 inhibition in MMCs occurs downstream of Ikaros/Aiolos reduction and suggest that IRF4 is a transcriptional target of Ikaros and/or Aiolos [7, 8, 13]
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