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PAX5/TEL Acts as a Transcriptional Repressor Causing Down-modulation of CD19, Enhances Migration to CXCL12, and Confers Survival Advantage in pre-BI Cells

¹ Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy; ² Vita-Salute San Raffaele University, Milan, Italy; and ³ University of Basel, Basel, Switzerland

Requests for reprints: Giovanni Cazzaniga, Centro Ricerca Tettamanti, Clinica Pediatrica Università di Milano-Bicocca, Ospedale San Gerardo, Avancorpo Sett. C, Piano Terra, via Pergolesi 33, 20052 Monza, Italy. Phone: 39-39233-2232/3661; Fax: 39-39233-2167; E-mail: gianni.cazzaniga{at}pediatriamonza.it.

PAX5 is a transcription factor essential for B-cell development. Recently, it has been found as a frequent target of aberrancies in childhood acute lymphoblastic leukemia (ALL; 30% of B cell ALL cases), showing monoallelic loss, point mutations, or chromosomal translocations. The role of these aberrancies is still poorly understood. We previously cloned the PAX5/TEL fusion gene in a patient affected by B-cell precursor ALL with a t(9;12) translocation. This is the first report investigating the molecular and functional roles of PAX5/TEL protein in vitro from murine wild-type pre-BI cells. We showed that PAX5/TEL protein acts as an aberrant transcription factor with repressor function, recruiting mSin3A, down-regulating B220, CD19, BLNK, MB-1, FLT3, and µ heavy chain expression, thus suggesting a block on B-cell differentiation. In a PAX5-deficient context, the presence of PAX5/TEL did not replace PAX5 functions. PAX5/TEL protein enhances cell migration towards CXCL12, with the overexpression of CXCR4. Moreover, the presence of the fusion gene overcomes interleukin-7 withdrawal and interferes with transforming growth factor-β1 pathway, inducing resistance and conferring cells an advantage in proliferation and survival. Thus, in vitro, the PAX5/TEL protein has a dominant effect on wild-type PAX5, interferes with the process of B-cell differentiation and migration, and induces resistance to apoptosis. Taken together, these phenomena likely represent key events in the process of B-cell transformation. [Cancer Res 2008;68(1):181–9]