A c-Myc and Surface CD19 Signaling Amplification Loop Promotes B Cell Lymphoma Development and Progression in Mice

Abstract

Malignant B cells responding to external stimuli are likely to gain a growth advantage in vivo. These cells may therefore maintain surface CD19 expression to amplify transmembrane signals and promote their expansion and survival. To determine whether CD19 expression influences this process, Eμ-Myc transgenic (c-MycTg) mice that develop aggressive and lethal B cell lymphomas were made CD19 deficient (c-MycTgCD19−/−). Compared with c-MycTg and c-MycTgCD19+/− littermates, the median life span of c-MycTgCD19−/− mice was prolonged by 81–83% (p < 0.0001). c-MycTgCD19−/− mice also lived 42% longer than c-MycTg littermates following lymphoma detection (p < 0.01). Tumor cells in c-MycTg and c-MycTgCD19−/− mice were B lineage derived, had a similar phenotype with a large blastlike appearance, invaded multiple lymphoid tissues, and were lethal when adoptively transferred into normal recipient mice. Importantly, reduced lymphomagenesis in c-MycTgCD19−/− mice was not due to reductions in early B cell numbers prior to disease onset. In mechanistic studies, constitutive c-Myc expression enhanced CD19 expression and phosphorylation on active sites. Reciprocally, CD19 expression in c-MycTg B cells enhanced c-Myc phosphorylation at regulatory sites, sustained higher c-Myc protein levels, and maintained a balance of cyclin D2 expression over that of cyclin D3. These findings define a new and novel c-Myc:CD19 regulatory loop that positively influences B cell transformation and lymphoma progression.

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

“…It was, however, robustly induced upon SHP2 re-expression and could form a SHP2-dependent positive feedback loop that enhanced the transcription factor c-Myc and oncogenic RAS expression in some solid cancers. 30 Because the well-known synergy of cMyc and CD19 aberrant expression in Eμ-Myc transgenic mice was necessary for malignant B-cell transformation, 19 we examined using immunoblot analyses, whether SHP2 commonly contributed to the reciprocal regulation of CD19 and c-Myc by transcriptional activation and subcellular localization in GC lymphoma cells. As expected, lack of SHP2 resulted in suppression of both CD19 and c-Myc protein and their activation in GC lymphoma cells ( Figure 5A), whereas CD19 knockdown had no effect on the expression of SHP2 in GC lymphoma cells but significantly inhibited its Tyr542 phosphorylation in…”

“…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. 19,20 Chromosomal overexpression of translocation-elicited c-Myc induces the transcription of cyclin and cyclin-dependent kinase (CDK) genes which also relies significantly on CD19/ERK cascade-mediated phosphorylation of c-Myc on Ser62. 19 Specifically, CD19-mediated MYC/IGH translocation-induced (MYC/IGH+) B-cell lymphomagenesis can be inhibited by deleting the scaffold protein kinase suppressor of RAS-1 (KSR1) or treatment with MEK/ERK inhibitors.…”

“…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.…”

“…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. 19,20 Chromosomal overexpression of translocation-elicited c-Myc induces the transcription of cyclin and cyclin-dependent kinase (CDK) genes which also relies significantly on CD19/ERK cascade-mediated phosphorylation of c-Myc on Ser62.…”

“…19,20 Chromosomal overexpression of translocation-elicited c-Myc induces the transcription of cyclin and cyclin-dependent kinase (CDK) genes which also relies significantly on CD19/ERK cascade-mediated phosphorylation of c-Myc on Ser62. 19 Specifically, CD19-mediated MYC/IGH translocation-induced (MYC/IGH+) B-cell lymphomagenesis can be inhibited by deleting the scaffold protein kinase suppressor of RAS-1 (KSR1) or treatment with MEK/ERK inhibitors. 20 Nevertheless, it remains unclear whether CD19 expression itself contributes alone to the regulation of c-Myc protein stability and activity in GC lymphoma, or whether CD19 expression is directly regulated by c-Myc transcriptional activity.…”