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


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.
Department of General Internal Medicine, University Hospital, Innsbruck, Austria.
Wolfgang
W
Eisterer
Oliver
O
Bechter
Ola
O
Söderberg
Kenneth
K
Nilsson
Maria
M
Terol
Richard
R
Greil
Josef
J
Thaler
Manfred
M
Herold
Lothar
L
Finke
Ursula
U
Günthert
Emilio
E
Montserrat
Reinhard
R
Stauder
D049109:Cell Proliferation; D003001:Cloning, Molecular; D004247:DNA / Q000096:biosynthesis; D018450:Disease Progression; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000175:diagnosis* / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D012995:Solubility; D014407:Tumor Cells, Cultured
D018960:Hyaluronan Receptors; D004247:DNA