title: Targeting the proliferative and chemoresistant compartment in chronic lymphocytic leukemia by inhibiting survivin protein.
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.
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Purroy
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Abrisqueta
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Carabia
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Carpio
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Calpe
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Palacio
authors.affiliation: Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Castellví
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Laboratory of Experimental Hematology, Department of Hematology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Bosch
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D000069461:Bendamustine Hydrochloride; D001854:Bone Marrow Cells / Q000166:cytology; D019013:CD40 Antigens / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000737:chemistry; D009588:Nitrogen Mustard Compounds / Q000737:chemistry; D017154:Stromal Cells / Q000166:cytology; D000077022:Survivin; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D019013:CD40 Antigens; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D009588:Nitrogen Mustard Compounds; D000077022:Survivin; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine; C523798:sepantronium