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Int J Biol Sci 2022; 18(7):2670-2682. doi:10.7150/ijbs.69615 This issue Cite

Research Paper

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

Jay Patel¹, Dan Xun², Karen Creswell², Daniel K. Kim¹, Matthew Wu¹, Jung-Won Hwang¹, Taylor S. Kim¹, Shivani Bansal¹, Sung-Hyeok Hong³, Susana Galli³, Hyun-Jung Kim⁴, Chuxia Deng⁵, Stephen W. Byers^1✉, Mi-Hye Lee^1,6✉

1. Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
2. Flow Cytometry Shared Resource, Georgetown University Medical Center, Washington, DC, USA.
3. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, USA.
4. Department of Molecular Genetics and Dental Pharmacology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, South Korea.
5. Faculty of Health Sciences, University of Macau, Macau SAR, China.
6. Department of Biology and Center for Cell Reprogramming, Georgetown University, Washington, DC, USA.

✉ Corresponding authors: Dr. Mi-Hye Lee, Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road, NW, New Research Building, Room E415, Washington, D.C. 20057, USA., Phone: +1-202-687-2820; E-mail: ml663edu; Dr. Stephen W. Byers, Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, 3970 Reservoir Road, NW, New Research Building, Room E415, Washington, D.C. 20057, USA., Phone: +1-202-687-1813; Fax: +1-202-687-7505; E-mail: byerssedu. More

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.

Keywords: RARRES1, B cell, Follicular Lymphoma, UPR, HSR, Metabolism

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