Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferating in vivo
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Noelia Purroy1, Pau Abrisqueta1, Júlia Carabia1, Cecilia Carpio1, Carles Palacio1, Francesc Bosch1,* and Marta Crespo1,*
1 Laboratory of Experimental Hematology, Department of Hematology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
* These authors contributed equally to this work
Marta Crespo, email:
Keywords: CLL, co-culture, proliferation, immunophenotype, chemoresistance, ZAP-70
Received: September 19, 2014 Accepted: December 02, 2014 Published: December 03, 2014
Chronic lymphocytic leukemia (CLL) cells residing in the bone marrow (BM) and in secondary lymphoid tissues receive survival and proliferative signals from the microenvironment, resulting in persistence of residual disease after treatment. In this study, we characterized primary CLL cells cultured with BM stromal cells, CD40 ligand and CpG ODN to partially mimic the microenvironment in the proliferative centers. This co-culture system induced proliferation and chemoresistance in primary CLL cells. Importantly, co-cultured primary CLL cells shared many phenotypical features with circulating proliferative CLL cells, such as upregulation of ZAP-70 and CD38 and higher CD49d and CD62L expression. This indicates aggressiveness and capability to interact with surrounding cells, respectively. In addition, levels of CXCR4 were decreased due to CXCR4 internalization after CXCL12 stimulation by BM stromal cells. We suggest that this co-culture system can be used to test drugs and their combinations that target the proliferative and drug resistant CLL cells.
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