Jourdan Michel, Cren Maïlys, Schafer Peter, Robert Nicolas, Duperray Christophe, Vincent Laure, Ceballos Patrice, Cartron Guillaume, Rossi Jean-François, Moreaux Jérôme, Chopra Rajesh, Klein Bernard
INSERM, U1040, Montpellier, France.
CNRS UPR1142, Institute of Human Genetics, Montpellier, France.
Oncotarget. 2016 May 10;7(19):28096-111. doi: 10.18632/oncotarget.8581.
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.
沙利度胺、来那度胺和泊马度胺极大地改善了多发性骨髓瘤患者的治疗结果。然而，它们对浆细胞（骨髓瘤细胞的健康对应物）的影响尚不清楚。在此，我们使用体外模型研究了来那度胺对正常人浆细胞生成的影响。来那度胺抑制前浆母细胞和早期浆细胞的生成，同时对浆母细胞的产生有中度影响。它还降低了浆母细胞和早期浆细胞中Ikaros、Aiolos和IRF4转录因子的表达水平。这表明它们对来那度胺的不同敏感性并非由于Ikaros或Aiolos降解的差异。来那度胺还抑制长寿浆细胞的生成，但一旦生成，并不会损害它们的长期存活。最后这一观察结果与以下发现一致：来那度胺治疗3至18个月并不影响同种异体移植的多发性骨髓瘤患者的骨髓健康浆细胞计数。我们的研究结果应促使人们去调查多发性骨髓瘤患者中来那度胺耐药是否可能与对来那度胺不太敏感的恶性浆母细胞或长寿浆细胞的出现有关。
