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Chronic Lymphocytic Leukemia

Targeting the proliferative and chemoresistant compartment in chronic lymphocytic leukemia by inhibiting survivin protein

Leukemia volume 28, pages 1993–2004 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI 11/00792) (FB). NP is a recipient of a PhD fellowship granted by Institut de Recerca Vall d’Hebron. CC is supported by a grant from Sociedad Española de Hematología y Hemoterapia (SEHH). MC holds a contract from Ministerio de Economía y Competitividad (MINECO) (RYC-2012-12018).

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  1. M Crespo and F Bosch: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Laboratory of Experimental Hematology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain

    N Purroy, P Abrisqueta, J Carabia, C Carpio, E Calpe, C Palacio, M Crespo & F Bosch

  2. Department of Pathology, Vall d’Hebron University Hospital, Barcelona, Spain

    J Castellví

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  1. N Purroy
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Purroy, N., Abrisqueta, P., Carabia, J. et al. Targeting the proliferative and chemoresistant compartment in chronic lymphocytic leukemia by inhibiting survivin protein. Leukemia 28, 1993–2004 (2014). https://doi.org/10.1038/leu.2014.96

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