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Expression of Erythropoietin Receptor and In vitro Functional Effects of Epoetins in B-Cell Malignancies

Authors' Affiliations: ¹ Departments of Oncology and Pathology, Karolinska Institutet and ² Departments of Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden; ³ Department of Immunology, Semnan Medical University, Semnan, Iran; ⁴ Roche Pharmaceutical Research, Department of Biology, Penzberg, Germany; and ⁵ Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

Requests for reprints: Anders Österborg, Department of Oncology, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. Phone: 46-8-517-755-08; Fax: 46-8-318-327; E-mail: anders.osterborg{at}karolinska.se.

Purpose: Erythropoietin (EPO) and EPO receptor (EPO-R) expression have been reported in solid tumors and are claimed to regulate tumor growth; however, no data have been published on this issue in B-cell malignancies or normal lymphoid cells. This report describes genomic/protein EPO-R expression and in vitro effects of recombinant human EPO (epoetin) in B-cell chronic lymphocytic leukemia (B-CLL), mantle-cell lymphoma (MCL), and multiple myeloma (MM).

Experimental Design: Blood samples were obtained from patients with B-CLL, MCL, and healthy volunteers, and bone marrow was obtained from MM patients. EPO-R mRNA was detected by reverse transcription-PCR. EPO-R surface expression was investigated by flow cytometry using digoxigenin-labeled epoetin and polyclonal rabbit anti–EPO-R antibody for intracellular receptor. Tumor cell stimulation was determined in vitro using [³H]thymidine incorporation and CD69 expression after exposure to epoetin or ß or darbepoetin .

Results: EPO-R mRNA was detected in mononuclear cells from 32 of 41 (78%) B-CLL and 5 of 7 (71%) MCL patients, and 21 of 21 (100%) MM samples. Expression was also detected in highly purified T cells from six of eight B-CLL patients, four of four MM patients, and normal donor B and T cells. Surface EPO-R protein was not detected. Intracellular EPO-R staining with anti–EPO-R antibodies was unspecific. No tumor-stimulatory effect was observed with high epoetin concentrations.

Conclusions: EPO-R gene is frequently expressed in lymphoid malignancies and normal B and T cells. However, there was no surface protein expression and no epoetin-induced in vitro stimulation of tumor B cells, indicating that epoetin therapy in vivo is likely to be safe in patients with lymphoid malignancies.