Inversely Association of the Aiolos Transcription Factor with Clinical Progression in Chronic Lymphocytic Leukemia.

Introduction:Aiolos encode a hemopoietic-specific zinc-finger transcription factor that is an important regulator of lymphocyte differentiation and plays a critical role in regulating B-cell development. RT-PCR analysis of the Aiolos gene expression revealed 16 Aiolos splicing variants, which have been named according to the exons missing from the full-length isoform. Recent data suggest that over 80% of expressed Aiolos in normal as well as in malignant B-cells is of the hAio1 type. Therefore, we investigated Aiolos mRNA expression (hAio1 type) in a large cohort with 155 patients along with the most commonly used biological markers in order to assess its role in risk prediction in B-CLL.

Methods and Results: The total amount of Aiolos transcripts in B-cells of 155 CLL patients using normal peripheral blood mononuclear cells represented a continuum ranging from 2.5- to 37-fold upregulation compared to that of normal B-cells, with a median of 20- fold upregulation. Moreover, Aiolos expression in B-CLL was significantly upregulated compared to cells of AML (113-fold; p<0.0001), ALL (14-fold; p=0.0024), CML (154- fold; p<0.0001), multiple myeloma (38-fold; p=0.0018) or NHL (16-fold; p<0.0001) suggesting that this Aiolos transcript is highly expressed specifically in B-CLL cells Patients with high Aiolos expression (according to ROC-analysis) had a significantly longer treatment-free survival (TFS) and overall survival (OS) than patients with low Aiolos expression (median TFS: 119 versus 45 months, p=0.005; median OS: 321 versus 244 months, p=0.0065). Evaluation of several disease characteristics in association with the Aiolos expression status of the patients’ B-CLL cells showed no significant differences for ZAP-70 expression (p=0.28), CD38 expression (p=0.067), IgVH status (p=0.49) and Binet stage (p=0.13) suggesting no correlation of Aiolos expression with these already established adverse prognostic factors. In multivariate analysis low Aiolos expression was an independent prognostic factor with significance for trend (hazard ratio 1.413; p=0.069). Sequential analyses in a subset of 10 CLL patients revealed that Aiolos expression was relatively stable over time in the majority of patients.

Conclusions: Here we demonstrate for the first time that the level of Aiolos expression is correlated with prognosis in B-CLL. The exact causes and consequences of this upregulation on the survival of CLL B-cells and the demonstrated better prognosis have yet to be determined. However, Aiolos may function as a tumor suppressor by controlling the cell cycle and DNA replication.