PAX5/TEL Causes Down Modulation of B-Lineage Specific Genes, and Enhances Migration to CXCL12 in preBI Cells.

PAX5 is a transcription factor essential for B-cell development. Recently, it has been found as frequent target of abnormalities in childhood ALL (30% of B-cell precursor ALL cases), showing monoallelic loss, point mutations or chromosomal translocations. The role of these lesions is still poorly understood. We previously cloned the PAX5/TEL fusion gene in a patient affected by B-cell precursor ALL with t(9;12) translocation. We investigated the functional roles of PAX5/TEL protein in vitro, in murine wild type preBI cells, primary cells derived from a wild type mouse and positive for B220, cKIT and CD19 antigens.We demonstrated that the PAX5/TEL protein acts as a transcriptional repressor, down regulating not only CD19, but also other B-lineage specific genes, such as BLNK and MB-1. In addition, PAX5/TEL down regulates FLT3, B220 and μ heavy chain expression, and it does not activate MCSFR. Moreover in PAX5^−/− preBI cells, PAX5/TEL did not restore CD19 expression. Comprehensively, these findings suggest that the fusion protein functions as a dominant repressor of transcription on many PAX5-target genes. It is known that CXCL12/SDF1 is a growth factor promoting B-cell progenitor proliferation, acting as a chemo attractant to the bone marrow. In several hematopoietic malignancies, tumor cells express CXCR4, and that the CXCL12-CXCR4 axis may influence the biology of tumor, favoring the metastasis process and the tumor proliferation. Indeed, we demonstrated that PAX5/TEL enhances cell migration towards CXCL12, with over-expression of CXCR4. These phenomena could indicate that leukemic cells carrying PAX5/TEL are able to access to niches that are normally restricted to progenitor cells, and thereby reside in a microenvironment that favours their growth and survival, although this finding must be proved in vivo. Together with previous evidences on the PAX5/TEL capacity to overcome IL7 withdrawal and to interfere with TGFbeta1 pathway, we conclude that PAX5/TEL induces resistance to apoptosis and interferes with the processes of B-cell differentiation and migration. Taken together, these phenomena likely represent key events in the process of B-cell transformation.