Overexpression of the proneural transcription factor ASCL1 in chronic lymphocytic leukemia with a t(12;14)(q23.2;q32.3).

Background: Translocations of the locus on 14q32.3 are present in about 8% of patients with chronic lymphocytic leukemia (CLL) and contribute to leukemogenesis by deregulating the expression of the -partner genes. Identification of these genes and investigation of the downstream effects of their deregulation can reveal disease-causing mechanisms.

Case Presentation: We report on the molecular characterization of a novel t(12;14)(q23.2;q32.3) in CLL. As a consequence of the rearrangement was brought into proximity of the IGHJ-Cμ enhancer and was highly overexpressed in the aberrant B-cells of the patient, as shown by qPCR and immunohistochemistry. encodes for a transcription factor acting as a master regulator of neurogenesis, is overexpressed in neuroendocrine tumors and a promising therapeutic target in small cell lung cancer (SCLC). Its overexpression has also been recently reported in acute adult T-cell leukemia/lymphoma.To examine possible downstream effects of the upregulation in CLL, we compared the gene expression of sorted CD5 cells of the translocation patient to that of CD19 B-cells from seven healthy donors and detected 176 significantly deregulated genes (Fold Change ≥2, FDR  ≤ 0.01). Deregulation of 55 genes in our gene set was concordant with at least two studies comparing gene expression of normal and CLL B-lymphocytes. , a well-established ASCL1 target in the nervous system and SCLC, was the gene with the strongest upregulation (Fold Change = 209.4, FDR  = 1.37E-4). encodes for a transcriptional repressor with extranuclear functions, implicated in neuroendocrine differentiation and overexpressed in the majority of neuroendocrine tumors. It was previously shown to be induced in CLL cells but not in normal B-cells upon treatment with IL-4 and to be overexpressed in CLL cells with unmutated versus mutated genes. Its role in CLL is still unexplored.

Conclusion: We identified as a novel -partner gene in CLL. The neural transcription factor was strongly overexpressed in the patient's CLL cells. Microarray gene expression analysis revealed the strong upregulation of , a prominent target, which was previously shown to be induced in CLL cells upon IL-4 treatment. We propose further investigation of the expression and potential role of in CLL.