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In order to sustain proficient life-long hematopoiesis, hematopoietic stem cells (HSCs) must possess robust mechanisms to preserve their quiescence and genome integrity. DNA-damaging stress can perturb HSC homeostasis by affecting their survival, self-renewal, and differentiation. Ablation of the kinase ataxia telangiectasia mutated (ATM), a master regulator of the DNA damage response, impairs HSC fitness. Paradoxically, we show here that loss of a single allele of Atm enhances HSC functionality in mice. To explain this observation, we explored a possible link between ATM and the tumor suppressor phosphatase and tensin homolog (PTEN), which also regulates HSC function. We generated and analyzed a knockin mouse line ([Pten.sup.S398A/S398A]), in which PTEN cannot be phosphorylated by ATM. Similar to [Atm.sup.+/-], [Pten.sup.S398A/S398A] HSCs have enhanced hematopoietic reconstitution ability, accompanied by resistance to apoptosis induced by genotoxic stress. Single- cell transcriptomic analyses and functional assays revealed that dormant [Pten.sup.S398A/S398A] HSCs aberrantly tolerate elevated mitochondrial activity and the accumulation of reactive oxygen species, which are normally associated with HSC priming for self-renewal or differentiation. Our results unveil a molecular connection between ATM and PTEN, which couples the response to genotoxic stress and dormancy in HSCs., Introduction Life-long hematopoiesis is required to produce all the blood cell types that maintain vital functions such as immunity, tissue repair, and oxygen transport. Hematopoietic dysregulation can have severe consequences [...]

Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORγt, T‐bet, Gata3 and PPARγ have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IκB protein family member Bcl‐3 suppresses RORγt+ Treg accumulation. The suppressive effect of Bcl‐3 was particularly evident in the mouse immune tolerance model of anti‐CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl‐3 specifically in Tregs was sufficient to boost RORγt+ Treg formation and resistance of mice to dextran sulfate sodium‐induced colitis. We further demonstrate the suppressive effect of Bcl‐3 on RORγt+ Treg differentiation in vitro. Our results reveal a novel role of nuclear factor‐kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy. [ABSTRACT FROM AUTHOR]

Bcl‐3 is an atypical member of the IκB family that modulates NF‐κB activity in nuclei. lpr mice carry the lpr mutation in Fas, resulting in functional loss of this death receptor; they serve as models for lupus erythematosus and autoimmune lymphoproliferation syndrome (ALPS). To explore the biologic roles of Bcl‐3 in this disease model, we generated BL6/lpr mice lacking Bcl‐3. Unlike lpr mice on an MRL background, BL6/lpr mice present with very mild lupus‐ or ALPS‐like phenotypes. Bcl‐3 KO BL6/lpr mice, however, developed severe splenomegaly, dramatically increased numbers of double negative T cells — a hallmark of human lupus, ALPS, and MRL/lpr mice — and exhibited inflammation in multiple organs, despite low levels of autoantibodies, similar to those in BL6/lpr mice. Loss of Bcl‐3 specifically in T cells exacerbated select lupus‐like phenotypes, specifically organ infiltration. Mechanistically, elevated levels of Tnfα in Bcl‐3 KO BL6/lpr mice may promote lupus‐like phenotypes, since loss of Tnfα in these mice reversed the pathology due to loss of Bcl‐3. Contrary to the inhibitory functions of Bcl‐3 revealed here, this regulator has also been shown to promote inflammation in different settings. Our findings highlight the profound, yet highly context‐dependent roles of Bcl‐3 in the development of inflammation‐associated pathology. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) exert inhibitory function under various physiological conditions and adopt diverse characteristics following environmental cues. Multiple subsets of Tregs expressing master transcription factors of helper T cells such as RORγt, T-bet, Gata3 and PPARγ have been characterized, but the molecular mechanism governing the differentiation of these subsets remains largely unknown. Here we report that the atypical IκB protein family member Bcl-3 suppresses RORγt + Treg accumulation. The suppressive effect of Bcl-3 was particularly evident in the mouse immune tolerance model of anti-CD3 therapy. Using conditional knockout mice, we illustrate that loss of Bcl-3 specifically in Tregs was sufficient to boost RORγt + Treg formation and resistance of mice to dextran sulfate sodium-induced colitis. We further demonstrate the suppressive effect of Bcl-3 on RORγt + Treg differentiation in vitro. Our results reveal a novel role of nuclear factor-kappa B signaling pathways in Treg subset differentiation that may have clinical implications in immunotherapy., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

As the most mutated gene in cancer, it is no surprise that TP53 has been the center of cancer biology discourse since its discovery in the late 1970s. Although early demonstrations of p53's role in the modulation of cell proliferation and survival solidified its classification as a tumor suppressor and transcription factor, our conceptualization of p53 is ever-evolving. Here, we present novel evidence of the role of alternative splicing isoforms, truncating/separation-of-function mutations, and hotspot silent mutations in the regulation of p53's activities.