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.

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

“…This link was strengthened by the observation that sIgM stimulation enhanced both CD19 surface expression and responsiveness. These data are in line with a recent study that established a linkage between the levels of CD19 expression and lymphoma progression (43). Ag stimulation is considered to be a key mediator in the development and progression of LPD (45).…”

“…Further support for the existence of two modes of signaling via the BCR can be found in the observation that the levels of the activation marker CD86 were elevated in a similar manner both in the CD19-N and CD19-R cells in response to sIgM stimulation, but only the latter were able to aggregate in response to CD19 engagement. Interestingly, dissociated signaling between CD19 and other components of the BCR is supported by a recent study in B cell lymphomas (43). CD19 is able to provoke both Akt phosphorylation and cellular aggregation.…”

“…However, we did not find higher frequency of Ki-67 + cells in the CD19-R fraction, indicating that this subpopulation is not necessarily an actively proliferating subclone of the disease. Accordingly, Chung et al (43) recently showed that CD19 levels correlate with c-myc-activated genes, and that CD19 is a major regulator of c-myc expression independent of BCR signaling, in a manner that is negatively correlated with the survival of human lymphoma patients. In this study, we show a similar correlation between the levels of CD19 expression, the levels of c-myc, and also with the ability of the cells to respond to CD19 engagement.…”

Conference Scene: Recent Developments in the Understanding and Treatment of Hematological Malignancies

“…In this case, the CAR was created against CD19, which is found on the surface of normal and malignant B cells and is a popular target for gene therapy treatments against B-cell cancers. In addition it has been suggested that CD19 causes the upregulation of the MYC oncoprotein through the PAX5 transcription factor [7]. In this study, 11 patients received the T cells, all had shown multiple relapses of acute lymphoblastic leukemia (ALL; n = 4) or B-cell lymphoma (n = 7) after autologous (n = 3), allogenic (n = 3) or cord blood (n = 1) hematopoietic stem cell transplantation.…”

Critical role of SHP2 (PTPN11) signaling in germinal center-derived lymphoma

“…Co-aggregate B-cell receptor and CD19/CD21 co-receptors are required for the survival of both resting and cycling B cells by regulating the cellular accumulation of the anti-apoptotic protein Bcl-2. 16,17 Additionally the B-cell receptor, by stabilizing the amount and activity of the oncoprotein c-Myc, 18,19 might facilitate B-cell lymphomagenesis through the CD19/RAS/ERK pathway, which can promote the expression of anti-apoptotic proteins. 19,20 Indeed, previous experimental data acquired through the use of Eμ-Myc transgenic mice demonstrated that the c-Myc/ERK/CD19 feedback signaling loop is important for the malignant transformation of B cells and in determining the severity of lymphomas.…”