title: CD19 is a major B cell receptor-independent activator of             MYC-driven B-lymphomagenesis.
abstract: PAX5, a B cell-specific transcription factor, is overexpressed             through chromosomal translocations in a subset of B cell lymphomas. Previously, we had             shown that activation of immunoreceptor tyrosine-based activation motif (ITAM) proteins             and B cell receptor (BCR) signaling by PAX5 contributes to B-lymphomagenesis. However,             the effect of PAX5 on other oncogenic transcription factor-controlled pathways is             unknown. Using a MYC-induced murine lymphoma model as well as MYC-transformed human B             cell lines, we found that PAX5 controls c-MYC protein stability and steady-state levels.             This promoter-independent, posttranslational mechanism of c-MYC regulation was             independent of ITAM/BCR activity. Instead it was controlled by another PAX5 target,             CD19, through the PI3K-AKT-GSK3β axis. Consequently, MYC levels in B cells             from CD19-deficient mice were sharply reduced. Conversely, reexpression of CD19 in             murine lymphomas with spontaneous silencing of PAX5 boosted MYC levels, expression of             its key target genes, cell proliferation in vitro, and overall tumor growth in vivo. In             human B-lymphomas, CD19 mRNA levels were found to correlate with those of MYC-activated             genes. They also negatively correlated with the overall survival of patients with             lymphoma in the same way that MYC levels do. Thus, CD19 is a major BCR-independent             regulator of MYC-driven neoplastic growth in B cell neoplasms.
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia 19104-4399, Pennsylvania, USA.
authors.forename: Elaine Y
authors.initials: EY
authors.lastname: Chung
authors.forename: James N
authors.initials: JN
authors.lastname: Psathas
authors.forename: Duonan
authors.initials: D
authors.lastname: Yu
authors.forename: Yimei
authors.initials: Y
authors.lastname: Li
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002461:Cell Line, Transformed; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D012334:RNA, Neoplasm / Q000235:genetics / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D018941:Antigens, CD19; C489428:Myc protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3