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Elevated levels of serum CD44 and E-cadherin predict an unfavourable outcome in myelodysplastic syndromes

Leukemia volume 20, pages 2064–2067 (2006)Cite this article

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal haematopoietic stem cell disorders with variable clinical course depending on ineffective haematopoiesis or transition to acute myeloid leukaemia (AML).1 Prognosis of MDS is closely correlated with bone marrow blast cell count, cytogenetic abnormalities and the degree of cytopenia, expressed in the International Prognosis Scoring System (IPSS). However, it is still difficult to predict survival in individual patients and the definition of additional parameters remains relevant for decisions in MDS-directed therapies.

The cell–cell adhesion molecule E-cadherin (120 kDa) and cell–matrix adhesion molecule CD44 (90 kDa) are involved in the regulation of haematopoiesis and are expressed on diverse types of mature blood cells and CD34+ stem cells.2, 3 Their aberrant expression plays a pivotal role in various solid and haematological malignancies like multiple myeloma, AML and lymphoma.4, 5, 6, 7 In malignant cells, these membrane-anchored proteins undergo activated proteolysis of the extracellular domain resulting in elevated serum levels of the soluble and bioactive polypeptides serum CD44 (sCD44) (25 kDa) or serum E-cadherin (sE-cad) (80–84 kDa).4 The multifunctional properties of both adhesion molecules with expression on diverse types of blood cells suggest a critical role in the pathogenesis of MDS. Takubo et al.8 described elevated serum levels of E-cadherin in a small MDS cohort (n=13) without analysis of its clinical significance. Similarly, there is also only one study reporting slightly increased CD44 serum levels in MDS (n=43),9 without subgroup analysis and no investigation of its impact on survival. In this report, the prognostic significance of serum levels of sCD44 standard (sCD44 s), the variant isoform CD44v6 (sCD44v6) and E-cadherin (sE-cad) was analysed in a cohort of 66 MDS patients. The study was approved by the local ethics committee and comprised clinical data and serum samples from consecutive, newly diagnosed and treatment-naive MDS patients who had given written informed consent before any study procedure. Patients with severely impaired liver or kidney function or elevated C-reactive protein were excluded from the study. MDS stage was classified according to the criteria of the French-American-British (FAB) group.1 Median age of patients was 71 years (range 19–93 years), female to male ratio 1:1.44. Fifteen patients presented with refractory anaemia (RA), five patients with RA with ringed sideroblasts (RARS), 21 patients with RA with excess of blasts (RAEB), 11 patients with RAEB in transition (RAEB-t), nine patients with chronic myelomonocytic leukaemia (CMML) and five patients with overt secondary acute leukaemia. The control group consisted of 19 age-matched persons without any evidence of inflammatory or neoplastic disease. Quantification of sCD44 s, sCD44v6 and sE-cad in serum samples was determined by enzyme-linked immunosorbent assay following the manufacturer's instruction (Bender MedSystems, Vienna, Austria; R&D Systems, Minneapolis, MS, USA). Statistical analysis was performed using SPSS 12.0 software (SPSS Inc., Chicago, IL, USA). The two-sided Mann–Whitney U-test was used to compare means between different FAB groups. Correlation coefficients were calculated with Spearman's rank correlation. Survivals were plotted by the Kaplan–Meier (KM) method and compared by the log-rank test. The observation period lasted at least 1 year. Cutoff levels for sCD44 s and sE-cad were defined as the mean level of healthy persons plus 2 s.d. Multivariate survival analysis was performed using the Cox proportional hazard model, including sCD44 s, sE-cad, age, sex, lactate dehydrogenase (LDH) and IPSS. Based on the hazard ratio, the mortality risk for an individual patient depending on levels of sCD44 s or sE-cad was calculated by hazard ratio (95% confidence interval) (increase of serum value in ng/ml).

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Acknowledgements

The excellent technical assistance of Silvia Blunder and Petra Schumacher is gratefully acknowledged. This study was supported by Dr Johannes und Hertha Tuba-Stiftung (RS)’, ‘Tiroler Verein zur Förderung der Krebsforschung (RS)’, ‘Katholnigg-Stiftung für MDS (HZ)’ and the Austrian National Bank, Project No. 10135 (HZ).

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  1. Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria

    J Loeffler-Ragg, S Skvortsov, M Herold & H Zwierzina

  2. Division of Haematology and Oncology, Innsbruck Medical University, Innsbruck, Austria

    M Steurer, B Kircher & R Stauder

  3. Department of Biostatistics and Documentation, Innsbruck Medical University, Innsbruck, Austria

    H Ulmer

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  1. J Loeffler-Ragg
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Loeffler-Ragg, J., Steurer, M., Ulmer, H. et al. Elevated levels of serum CD44 and E-cadherin predict an unfavourable outcome in myelodysplastic syndromes. Leukemia 20, 2064–2067 (2006). https://doi.org/10.1038/sj.leu.2404382

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