B cell activator PAX5 promotes lymphomagenesis through stimulation of B cell receptor signaling.
The presumed involvement of paired box gene 5 (PAX5) in B-lymphomagenesis is based largely on the discovery of Pax5-specific translocations and somatic hypermutations in non-Hodgkin lymphomas. Yet mechanistically, the contribution of Pax5 to neoplastic growth remains undeciphered. Here we used 2 Myc-induced mouse B lymphoma cell lines, Myc5-M5 and Myc5-M12, which spontaneously silence Pax5. Reconstitution of these cells with Pax5-tamoxifen receptor fusion protein (Pax5ER(TAM)) increased neoplastic growth in a hormone-dependent manner. Conversely, expression of dominant-negative Pax5 in murine lymphomas and Pax5 knockdown in human lymphomas negatively affected cell expansion. Expression profiling revealed that Pax5 was required to maintain mRNA levels of several crucial components of B cell receptor (BCR) signaling, including CD79a, a protein with the immunoreceptor tyrosine-based activation motif (ITAM). In contrast, expression of 2 known ITAM antagonists, CD22 and PIR-B, was suppressed. The key role of BCR/ITAM signaling in Pax5-dependent lymphomagenesis was corroborated in Syk, an ITAM-associated tyrosine kinase. Moreover, we observed consistent expression of phosphorylated BLNK, an activated BCR adaptor protein, in human B cell lymphomas. Thus, stimulation of neoplastic growth by Pax5 occurs through BCR and is sensitive to genetic and pharmacological inhibitors of this pathway.
Cozma
Diana
D
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6051, USA.
Yu
Duonan
D
Hodawadekar
Suchita
S
Azvolinsky
Anna
A
Grande
Shannon
S
Tobias
John W
JW
Metzgar
Michele H
MH
Paterson
Jennifer
J
Erikson
Jan
J
Marafioti
Teresa
T
Monroe
John G
JG
Atchison
Michael L
ML
Thomas-Tikhonenko
Andrei
A
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009368:Neoplasm Transplantation; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse; D011947:Receptors, Antigen, B-Cell
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