ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia.

Distal enhancers play critical roles in sustaining oncogenic gene-expression programs. We identify aberrant enhancer-like activation of GGAA tandem repeats as a characteristic feature of B-cell acute lymphoblastic leukemia (B-ALL) with genetic defects of the ETV6 transcriptional repressor, including ETV6-RUNX1+ and ETV6-null B-ALL. We show that GGAA repeat enhancers are direct activators of previously identified ETV6-RUNX1+/- like B-ALL "signature" genes, including the likely leukemogenic driver EPOR. When restored to ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA repeat enhancers, represses their acetylation, downregulates adjacent genes, and inhibits B-ALL growth. In ETV6-deficient B-ALL cells, we find that the ETS transcription factor ERG directly binds to GGAA microsatellite enhancers and is required for sustained activation of repeat enhancer-activated genes. Together, our findings reveal an epigenetic gatekeeper function of the ETV6 tumor suppressor gene and establish microsatellite enhancers as a key mechanism underlying the unique gene-expression program of ETV6-RUNX1+/- like B-ALL. SIGNIFICANCE: We find a unifying mechanism underlying a leukemia subtype-defining gene-expression signature that relies on repetitive elements with poor conservation between humans and rodents. The ability of ETV6 to antagonize promiscuous, nonphysiologic ERG activity may shed light on other roles of these key regulators in hematolymphoid development and human disease. See related commentary by Mercher, p. 2. This article is highlighted in the In This Issue feature, p. 1.

Smoking and degenerative spinal disease: A systematic review.

Smoking is a major cause of morbidity and mortality worldwide and is responsible for the death of more than 8 million people per year globally. Through a systematic literature review, we aim to review the harmful effects of tobacco smoking on degenerative spinal diseases (DSD). DSD is a debilitating disease and there is a need to identify if smoking can be an attributable contender for the occurrence of this disease, as it can open up avenues for therapeutic options. Sources such as PubMed and Embase were used to review literature, maintaining tobacco smoking and spinal diseases as inclusion factors, excluding any article that did not explore this relationship. Risk of bias was assessed using analysis of results, sample size and methods and limitations. Upon review of the literature, tobacco smoking was found to be a major risk factor for the occurrence of DSDs, particularly lumbar spinal diseases. Smokers also experienced a greater need for surgery and greater postoperative wound healing complications, increased pain perception, delay in recovery and decreased satisfaction after receiving surgery. These effects were noted along the entire spine. Many mechanisms of action have been identified in the literature that provide plausible pictures of how smoking leads to spinal degeneration, exploring possible primary targets which can open up opportunities to develop potential therapeutic agents. More studies on cervical and thoracic spinal degeneration would be beneficial in identifying the effect of nicotine on these spinal levels. Some limitations included insufficient sample size, inconclusive evidence and lack of sufficient repeat studies. However, there appears to be a sufficient amount of research on smoking directly contributing to lumbar spinal pathology.

Retinoic Acid Potentiates Orbital Tissues for Inflammation Through NF-κB and MCP-1.

Purpose: The orbit displays unique vulnerability to inflammatory conditions. The most prevalent of these conditions, thyroid eye disease (TED), occurs in up to 50% of patients with Graves' disease (GD). Whereas the pathology of both TED and GD is driven by autoantibodies, it is unclear why symptoms manifest specifically in the orbit. Methods: We performed retinoic acid treatment on both normal and TED patient-derived orbital fibroblasts (OFs) followed by mRNA and protein isolation, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, RNA sequencing, and Western blot analyses. Results: Both normal and TED patient-derived OFs display robust induction of monocyte chemoattractant protein 1 (MCP-1) upon retinoid treatment; TED OFs secrete significantly more MCP-1 than normal OFs. In addition, pretreatment of OFs with thiophenecarboxamide (TPCA-1) inhibits retinoid-induced MCP-1 induction, suggesting an NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)-dependent mechanism. We also found that treatment with cholecalciferol (vitamin D3) mitigates MCP-1 induction, likely because of competition between retinoic acid receptors (RARs) and vitamin D receptors (VDR) for their common binding partner retinoid nuclear receptors (RXRs). Conclusions: Retinoids that naturally accumulate in orbital adipose tissue can act on orbital fibroblasts to induce the expression of inflammation-associated genes. These data suggest a potential role for retinoids in sensitizing the orbit to inflammation.