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The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Patients with unmutatedIGHV(U-CLL) usually progress rapidly, whereas patients with mutatedIGHV(M-CLL) have a more indolent disease. The expression of several genes correlates closely with theIGHVmutational status and could be used to assess prognosis in CLL. We analyzed the prognostic relevance ofCOBLL1,LPL,andZAP70gene expression, which correlated withIGHVmutational status (p < 0.0001), in 117 CLL patients and established a prognostic parameter dividing the tested cohort according to the disease aggressiveness. Our prognostic parameter was validated on an independent cohort of 161 CLL patients and achieved a high accuracy (94%). Patients divided according to the prognostic parameter differ in overall survival and time to first treatment (p < 0.0001, HR  = 2.300/5.970, 95% CI: 1.587–3.450/4.621–15.86). Our approach provides a reliable alternative method to prognosis assessment viaIGHVmutational status analysis. [ABSTRACT FROM PUBLISHER]

The canonical Wnt pathway, dependent on β-catenin-controlled transcription, is the most explored Wnt pathway, known to drive the malignant transformation of multiple cell types. Several reports have suggested that this pathway also participates in chronic lymphocytic leukaemia ( CLL) pathogenesis. To get a better insight into the role of the Wnt/β-catenin pathway in CLL we analysed in detail the expression of the most overexpressed Wnt ligand, encoded by the WNT3 gene, in a well-defined cohort of 137 CLL patients. Our analysis demonstrated that (i) untreated patients with more aggressive disease (with a notable exception of patients with 11q deletion) express less WNT3, (ii) WNT3 declines with disease progression in a significant proportion of patients and (iii) low WNT3 was identified as a strong independent marker indicating shorter treatment-free survival in CLL patients with IGHV mutation. Interestingly, CLL-related lymphoid cell lines, but not stromal cells, failed to respond to the ligand-induced activation of the Wnt/β-catenin pathway. This opens the possibility that CLL cells use Wnt-3 to communicate with the cells in the microenvironment. We thus propose that the Wnt/β-catenin pathway plays a more complex role in CLL pathogenesis than previously anticipated. [ABSTRACT FROM AUTHOR]