Dataset Information

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

ABSTRACT: Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive Rarres1 knockout (Rarres1 ^-/-) mouse models to study RARRES1 function in vivo. Rarres1 ^-/- embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and survival, recapitulating RARRES1 function in immortalized cell lines. In two mouse strains, loss of Rarres1 led to a markedly increased dose-dependent incidence of follicular lymphoma (FL). Prior to lymphoma formation, Rarres1 ^-/- B cells have compromised activation, maturation, differentiation into antibody-secreting plasma cells, and cell cycle progression. Rarres1 ablation increased B cell survival and led to activation of the unfolded protein response (UPR) and heat shock response (HSR). Rarres1 deficiency had differential effects on cellular metabolism, with increased bioenergetic capacity in fibroblasts, and minor effects on bioenergetics and metabolism in B cells. These findings reveal that RARRES1 is a bona fide tumor suppressor in vivo and the deletion in mice promotes cell survival, and reduces B cell differentiation with B cell autonomous and non-autonomous functions.

SUBMITTER: Patel J

PROVIDER: S-EPMC9066096 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Patel Jay J Xun Dan D Creswell Karen K Kim Daniel K DK Wu Matthew M Hwang Jung-Won JW Kim Taylor S TS Bansal Shivani S Hong Sung-Hyeok SH Galli Susana S Kim Hyun-Jung HJ Deng Chuxia C Byers Stephen W SW Lee Mi-Hye MH

International journal of biological sciences 20220328 7

Retinoic acid receptor responder 1 (RARRES1) is among the most commonly methylated loci in multiple cancers. RARRES1 regulates mitochondrial and fatty acid metabolism, stem cell differentiation, and survival of immortalized cell lines in vitro. Here, we created constitutive Rarres1 knockout (Rarres1-/-) mouse models to study RARRES1 function in vivo. Rarres1-/- embryonic fibroblasts regulated tubulin glutamylation, cell metabolism, and sur ...[more]

PMID: 35541897

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Project description:Thymic lymphomas induced by Moloney murine leukemia virus (MMLV) have provided many examples of oncogene activation, but the role of tumor suppressor pathways in these tumors is less clear. These tumors display little evidence of loss of heterozygosity, and MMLV is only weakly synergistic with the Trp53 null genotype, suggesting that viral lymphomagenesis involves mechanisms which do not require mutational loss of Trp53 function. To explore this relationship in greater depth, we infected CD2-myc transgenic mice with MMLV and examined the role of Trp53 in the genesis of these tumors. Most (19 of 27) of the tumors from MMLV-infected, CD2-myc Trp53(+/-) mice retained the wild-type Trp53 allele in vivo while tumors of uninfected CD2-myc Trp53(+/-) mice invariably showed allele loss from a significant fraction of primary tumor cells. The functional integrity of the Trp53 gene in these tumors was indicated by ongoing allele loss or selection for mutational stabilization during in vitro propagation and by the radiosensitivity of selected Trp53(+/-) tumor cell lines. An inverse correlation was noted between retention of the wild-type Trp53 allele and expression of p19(ARF), providing further evidence of negative-feedback control of the latter by p53. However, expression of p19(ARF) does not appear to be counterselected in the absence of p53, and its integrity in Trp53(+/-) tumors was indicated by its transcriptional upregulation on Trp53 wild-type allele loss in vitro in selected tumor cell lines. The role of MMLV was investigated further by analysis of proviral insertion sites in tumors of CD2-myc transgenic mice sorted for Trp53 genotype. A proportion of tumors showed insertions at Runx2, an oncogene which has been shown to collaborate independently with CD2-myc and with the Trp53 null genotype, and at a novel common integration site (ptl-1) on chromosome 8. Genotypic analysis of the panel of tumors suggested that neither of these integrations is functionally redundant with loss of p53, but it appears that the combination of the MMLV oncogenic program with the CD2-myc oncogene relegates p53 loss to a late step in tumor progression or in vitro culture. While the means by which these tumors preempt the p53 tumor suppressor response remains to be established, this study provides further evidence that irreversible inactivation of this pathway is not a prerequisite for tumor development in vivo.

Dataset Information

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

Publications

Loss of RARRES1 function Promotes Follicular Lymphomagenesis and Inhibits B cell Differentiation in Mice.

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