Wnt5b Gene Expression Negative Prognostic Factor in CLL Patients

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American Association for Cancer Research #1139

Wnt5b expression: A novel candidate predictive factor for disease

evolution in chronic lymphocytic leukemia

Cristina Rabascio, Luca Saronni, Valentina Raia, Patrizia Mancuso,

Alice Agliano, Cinzia Massaro, e Laszlo, Giovanni elli,

Francesco Bertolini. European Institute of Oncology, Milan, Italy

Background: Molecular diagnostic tools offer the potential for

accurate prognostic road maps in patients with hematological

malignancies. Wnts are a large family of secreted glycoproteins

involved in cell proliferation, differentiation and oncogenesis. The

classical Wnt signaling cascade inhibits the activity of the enzyme

glycogen synthase kinase-3beta, augmenting beta-catenin translocation

to the nucleus and the transcription of target genes. Previous data

(Desheng et al PNAS 2004) suggested that the Wnt signaling pathway

contributes to a deficient apoptosis in chronic lymphocytic leukemia

(CLL).

Method: In this retrospective study we used the ABI PRISM 7000 Real

Time platform to analyze the Wnt5b gene expression in 24 newly

diagnosed CLL patients randomly chosen from our database. Patients

were treated with different treatment schedules. In addition, we

analyzed 9 hematological neoplastic cell lines and 18 healthy donors.

Wnt5b pathologic expression was then normalized against healthy

donors median expression (P/H).

Results: All healthy donors and cell lines and 15 CLL patients showed

Wnt5b expression, while 9 CLL patients were negative. After a median

follow up of 22 months (range 8-29), 6 patients were in complete

remission (CR), 11 were in stable disease (SD) and 7 had progressive

disease (PD). In this patient population, 14/15 patients (93%) with

Wnt5b basal expression were in PD or SD (p=0.01 vs patients in CR).

All patients who achieved a CR after therapy had no or very low Wnt5b

expression at diagnosis (median P/H=0, range 0-0.26), while SD or PD

patients had a median P/H ratio higher than 0.3 (range 0-10.52,

p=0.03). Since other investigators have described Wnt5b expression in

CD19+ neoplastic B cells, we next investigated Wnt5b expression in

CD19+, CD14+, CD3+ and CD56+ cells from healthy donors purified by

magnetic beads (purity >90%). In healthy donors Wnt5b was expressed

only in purified CD14+ monocyte cell fraction and not in CD19+ (B-

cells), CD3+ (T-cells) or CD56+ (NK-cells) or in the remaining CD14-

negative cell fraction.

Conclusion: In our CLL patient population, Wnt5b expression at

diagnosis was a negative predictive factor associated to disease

evolution. We are currently prospectively evaluating a larger patient

population to better assess in multivariate analysis the predictive

potential of this novel biomarker along with established prognostic

factors such as ZAP70 expression and mutational status.

The availability of this potential biologic prognostic indicator

might be of great importance for future risk-adapted treatments.

Further prospective studies evaluating the different technologic

aspects of its detection and correlation with other biological

markers (ZAP70 and mutational status) are clearly needed to confirm

our preliminary results.

Copyright © 2006 American Association for Cancer Research.