Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis

Abstract

A major transcriptional output of cells is ribosomal RNA (rRNA), synthesized by RNA polymerase I (Pol I) from multicopy rRNA genes (rDNA). Constitutive silencing of an rDNA fraction by promoter CpG methylation contributes to the stabilization of these otherwise highly active loci. In cancers driven by the oncoprotein Myc, excessive Myc directly stimulates rDNA transcription. However, it is not clear when during carcinogenesis this mechanism emerges, and how Myc-driven rDNA activation affects epigenetic silencing. Here, we have used the Eµ-Myc mouse model to investigate rDNA transcription and epigenetic regulation in Myc-driven B cell lymphomagenesis. We have developed a refined cytometric strategy to isolate B cells from the tumor initiation, promotion, and progression phases, and found a substantial increase of both Myc and rRNA gene expression only in established lymphoma. Surprisingly, promoter CpG methylation and the machinery for rDNA silencing were also strongly up-regulated in the tumor progression state. The data indicate a dichotomous role of oncogenic Myc in rDNA regulation, boosting transcription as well as reinforcing repression of silent repeats, which may provide a novel angle on perturbing Myc function in cancer cells.

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

“…B-cell development in the bone marrow was despite this not affected by M-100 treatment ( Supplemental Figure 3B ) and increased apoptosis of B-cells was not detected in vivo ( Supplemental Figure 3C ). In fact, B220 low cells were still present in spleens ( Supplemental Figure 3C ), which have been previously described as pre-tumor B-cells in this model (27,28). Besides, survivors from the M-100 cohort showed a significant decline in CD11b + myeloid cells and an absolute as well as a relative increase in CD3 + T-cells compared to the vehicle group ( Figure 1F, Supplemental Figure 3A ).…”

Targeting the MYC interaction network in B-cell lymphoma via histone deacetylase 6 inhibition

“…In fact, B220 low cells were still present in spleens (Supplemental Fig. 3C ), which have been previously described as pre-tumor B-cells in this model [ 27 , 28 ]. Besides, survivors from the M-100 cohort showed a significant decline in CD11b + myeloid cells and an absolute as well as a relative increase in CD3 + T-cells compared to the vehicle group (Fig.…”