PAX5/TEL acts as a transcriptional repressor causing down-modulation of CD19, enhances migration to CXCL12, and confers survival advantage in pre-BI cells.
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 mu 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-beta1 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.
Fazio
Grazia
G
Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
Palmi
Chiara
C
Rolink
Antonius
A
Biondi
Andrea
A
Cazzaniga
Giovanni
G
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D051925:CD79 Antigens / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000276:immunology; D015536:Down-Regulation; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D051757:PAX5 Transcription Factor / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D018941:Antigens, CD19; C113939:B cell linker protein; D051925:CD79 Antigens; D054377:Chemokine CXCL12; D015851:Interleukin-7; D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C526548:PAX5-TEL fusion protein, human; D012097:Repressor Proteins; D053773:Transforming Growth Factor beta1; D051941:fms-Like Tyrosine Kinase 3