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

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Retinoic acid receptor responder 1 (RARRES1) is frequently methylated in cancers.
• RARRES1 influences metabolism, stem cell differentiation, and cell survival.
• Its in vivo function remained largely uncharacterized.

Purpose of the Study:

• To investigate the in vivo role of RARRES1.
• To determine the impact of RARRES1 loss on cancer development and B cell biology.

Main Methods:

• Generated constitutive Rarres1 knockout mouse models (Rarres1^-/-).
• Analyzed embryonic fibroblasts and B cells from knockout mice.
• Assessed lymphoma incidence, B cell function, metabolism, and stress responses.

Main Results:

• Rarres1^-/- fibroblasts showed altered metabolism and tubulin glutamylation.
• Loss of Rarres1 significantly increased follicular lymphoma incidence in mice.
• Rarres1^-/- B cells exhibited impaired activation, maturation, differentiation, and cell cycle progression.
• RARRES1 deficiency promoted B cell survival, activating unfolded protein response and heat shock response.
• Metabolic effects were pronounced in fibroblasts but minor in B cells.

Conclusions:

• RARRES1 functions as a tumor suppressor in vivo.
• RARRES1 deficiency promotes B cell survival and impairs differentiation, contributing to lymphomagenesis.
• RARRES1 loss impacts cellular metabolism and stress responses, with differential effects on cell types.