MicroRNA Biogenesis Is Required for Myc-Induced B-Cell Lymphoma Development and Survival

Abstract

Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III-like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre + /Eμ-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre + /Dicer fl/fl /Eμ-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival. Cancer Res; 70(14); 6083-92. ©2010 AACR.

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

“…Further to this, monoallelic Dicer1 loss exerted an effect, which indicates that Dicer1 is also a haploinsufficient tumor suppressor gene. These findings are consistent with the role of Dicer1 in other tumor types (Arrate et al 2010;Lambertz et al 2010;Nittner et al 2012;Yoshikawa et al 2013;Zhang et al 2014).…”

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Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer

“…Total RNA was isolated using Trizol (Life Technologies) following the manufacturer's protocol. miRNA analysis was performed as previously reported by Arrate et al (2010). Briefly, the Taqman miRNA reverse transcription kit (Life Technologies) was used to make miRNA-specific cDNA.…”

MicroRNAs as B-cell lymphoma biomarkers

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