Tumor and Stem Cell Biology Inactivation of p53 Is Insufficient to Allow B Cells and B-Cell Lymphomas to Survive Without Dicer

Inactivation of p53, themaster regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III–like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to surviveDicerdeletion, suggesting that p53 lossmay protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletioninduced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditionalDicer knockout Em-myc transgenicmice.Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null Bcell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cremediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas. Cancer Res; 74(14); 3923–34. 2014 AACR.