RRC ID 44961
Author Purroy N, Abrisqueta P, Carabia J, Carpio C, Calpe E, Palacio C, Castellví J, Crespo M, Bosch F.
Title Targeting the proliferative and chemoresistant compartment in chronic lymphocytic leukemia by inhibiting survivin protein.
Journal Leukemia
Abstract Chronic lymphocytic leukemia (CLL) cells located in proliferation centers are constantly stimulated by accessory cells, which provide them with survival and proliferative signals and mediate chemotherapy resistance. Herein, we designed an experimental strategy with the aim of mimicking the microenvironment found in the proliferative centers to specifically target actively proliferating CLL cells. For this, we co-cultured CLL cells and bone marrow stromal cells with concomitant CD40 and Toll-like receptor 9 stimulation. This co-culture system induced proliferation, cell-cycle entry and marked resistance to treatment with fludarabine and bendamustine. Proliferating CLL cells clustered together showed a typical morphology of activated B cells and expressed survivin protein, a member of the inhibitor of apoptosis family that is mainly expressed by CLL cells in the proliferation centers. With the aim of specifically targeting actively proliferating and chemoresistant CLL cells, we investigated the effects of treatment with YM155, a small-molecule survivin inhibitor. YM155 treatment suppressed the co-culture-induced survivin expression and that was sufficient to inhibit proliferation and effectively induce apoptosis particularly in the proliferative subset of CLL cells. Interestingly, sensitivity to YM155 was independent from common prognostic markers, including 17p13.1 deletion. Altogether, these findings provide a rationale for clinical development of YM155 in CLL.
Volume 28(10)
Pages 1993-2004
Published 2014-10-1
DOI 10.1038/leu.2014.96
PII leu201496
PMID 24618734
MeSH Adult Aged Aged, 80 and over Antineoplastic Agents / chemistry* Apoptosis B-Lymphocytes / drug effects B-Lymphocytes / metabolism Bendamustine Hydrochloride Bone Marrow Cells / cytology CD40 Antigens / metabolism Cell Cycle Cell Proliferation Coculture Techniques Drug Resistance, Neoplasm* Female Gene Deletion Humans Imidazoles / chemistry Inhibitor of Apoptosis Proteins / metabolism* Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy* Leukocytes, Mononuclear / cytology Male Middle Aged Naphthoquinones / chemistry Nitrogen Mustard Compounds / chemistry Stromal Cells / cytology Survivin Toll-Like Receptor 9 / metabolism Vidarabine / analogs & derivatives Vidarabine / chemistry
IF 8.665
Times Cited 13
Human and Animal Cells UE6E7T-2(RCB2153)