Elevated levels of soluble CD44 are associated with advanced disease and in vitro proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia

Eisterer, Wolfgang; Bechter, Oliver; Söderberg, Ola; Nilsson, Kenneth; Terol, Maria; Greil, Richard; Thaler, Josef; Herold, Manfred; Finke, Lothar; Günthert, Ursula; Montserrat, Emilio; Stauder, Reinhard

doi:10.1016/j.leukres.2004.01.016

« Previous Next »Leukemia Research
Volume 28, Issue 10 , Pages 1043-1051, October 2004

Elevated levels of soluble CD44 are associated with advanced disease and in vitro proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia

Wolfgang Eisterer
- Department of General Internal Medicine, University Hospital, Innsbruck, Austria
Oliver Bechter
- Department of General Internal Medicine, University Hospital, Innsbruck, Austria
- Bechter O. and Söderberg O. contributed equally to the manuscript.
Ola Söderberg
- Department of Pathology, University of Uppsala, University Hospital, Uppsala, Sweden
- Bechter O. and Söderberg O. contributed equally to the manuscript.
Kenneth Nilsson
- Department of Pathology, University of Uppsala, University Hospital, Uppsala, Sweden
Maria Terol
- Department of Haematology, Hospital Clinic, Barcelona, Spain
Richard Greil
- Divison of Hematology and Oncology, University Hospital, Anichstr. 35, 6020 Innsbruck, Austria
Josef Thaler
- Department of General Internal Medicine, University Hospital, Innsbruck, Austria
Manfred Herold
- Department of General Internal Medicine, University Hospital, Innsbruck, Austria
Lothar Finke
- Delbrück Center for Molecular Medicine, Berlin, Germany
Ursula Günthert
- Basel Institute for Immunology, Basel, Switzerland
- Present address: Institute for Medical Microbiology, University of Basel, Basel, Switzerland.
Emilio Montserrat
- Department of Haematology, Hospital Clinic, Barcelona, Spain
Reinhard Stauder
- Divison of Hematology and Oncology, University Hospital, Anichstr. 35, 6020 Innsbruck, Austria
- Corresponding author. Tel.: +43-512-504-23255; fax: +43-512-504-23341.

Received 10 October 2003; accepted 14 January 2004.

Abstract

Purpose: Increased expression of the adhesion molecule CD44 has been associated with an unfavourable clinical outcome in lymphomas. We evaluated the prognostic value of soluble CD44 in B-cell chronic lymphocytic leukaemia (B-CLL) and analysed the source and regulation of CD44 secretion in B-CLL clones in vitro. Patients and methods: Levels of soluble CD44 standard (sCD44s) and of the soluble variant isoform CD44v6 (sCD44v6) were analysed by enzyme linked immuno sorbent assay. Highly purified B-CLL cells (98% CD19+CD3− cells) were stimulated in vitro by different combinations of thioredoxin (Trx), Staphylococcus aureus Cowan strain 1 (SAC), IL-2, IL-4, IL-10, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and by anti-CD40 mAbs presented on irradiated CD32L cells. Results: Serum levels of sCD44s and of sCD44v6 are significantly elevated in B-CLL patients (n=90) in comparison with normal persons (n=44) (P<0.001). Elevated levels of sCD44s and sCD44v6 are associated with an advanced disease as reflected by an extended lymph node involvement (P<0.02), an advanced Binet (P<0.03) and Rai stage (P<0.04) and chemotherapy requirement (P<0.02). High levels of sCD44s are associated with high leukocyte counts (P<0.04) and increased sCD44v6 is significantly associated with splenomegaly (P<0.002). In B-CLL sCD44s as well as sCD44v6 is shed from leukaemia cells as shown by in vitro cultures. Stimulation of B-CLL clones results in a proliferation-associated increased secretion of sCD44s (rho=0.7; P=0.0001) and of sCD44v6 (rho=0.5; P=0.005). B-CLL clones from advanced stage patients are characterised by an increased capacity for proliferation and CD44 production in comparison with early stage patients. Conclusions: Both sCD44s and sCD44v6 represent a reliable prognostic marker in B-CLL and may be involved in the pathogenesis of B-CLL.