Advancements in Spinal Cord Injury Repair: Insights from Dental-Derived Stem Cells.

Spinal cord injury (SCI), a prevalent and disabling neurological condition, prompts a growing interest in stem cell therapy as a promising avenue for treatment. Dental-derived stem cells, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), stem cells from the apical papilla (SCAP), dental follicle stem cells (DFSCs), are of interest due to their accessibility, minimally invasive extraction, and robust differentiating capabilities. Research indicates their potential to differentiate into neural cells and promote SCI repair in animal models at both tissue and functional levels. This review explores the potential applications of dental-derived stem cells in SCI neural repair, covering stem cell transplantation, conditioned culture medium injection, bioengineered delivery systems, exosomes, extracellular vesicle treatments, and combined therapies. Assessing the clinical effectiveness of dental-derived stem cells in the treatment of SCI, further research is necessary. This includes investigating potential biological mechanisms and conducting Large-animal studies and clinical trials. It is also important to undertake more comprehensive comparisons, optimize the selection of dental-derived stem cell types, and implement a functionalized delivery system. These efforts will enhance the therapeutic potential of dental-derived stem cells for repairing SCI.

Regulation of phosphoglycerate kinase 1 and its critical role in cancer.

Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis. This phenomenon is called the "Warburg effect". Phosphoglycerate kinase 1 (PGK1) is a key enzyme in aerobic glycolysis. PGK1 is involved in glucose metabolism as well as a variety of biological activities, including angiogenesis, EMT, mediated autophagy initiation, mitochondrial metabolism, DNA replication and repair, and other processes related to tumorigenesis and development. Recently, an increasing number of studies have proven that PGK1 plays an important role in cancer. In this manuscript, we discussed the effects of the structure, function, molecular mechanisms underlying PGK1 regulation on the initiation and progression of cancer. Additionally, PGK1 is associated with chemotherapy resistance and prognosis in tumour patients. This review presents an overview of the different roles played by PGK1 during tumorigenesis, which will help in the design of experimental studies involving PGK1 and enhance the potential for the use of PGK1 as a therapeutic target in cancer. Video Abstract.

Intravascular ultrasound provides additional insights in the hypertensive patients with focal renal artery fibromuscular dysplasia.

To date, few study has defined the exact role or utility of intravascular ultrasound (IVUS) in the diagnosis and treatment of renal artery fibromuscular dysplasia (FMD). We investigated whether using an IVUS would provide additional insights in the hypertensive patients with focal renal artery FMD. A prospective, observational study, including all patients with focal renal artery FMD admitted to the Ruijin hospital during 6 consecutive years (2015-2021). Based on IVUS imaging, focal FMD patients were classified as two subtypes: intima-media thickening (IMT) and negative remodeling (NR) of the whole vessel. A total of 36 consecutive patients (24 ± 7, 13-39 years) with focal renal artery FMD were enrolled. Angiographic unifocal type was present in 22 (61.1%) patients and tubular type was present in 14 (38.9%) patients. Among 22 patients with unifocal, IVUS showed that 18 (81.8%) had IMT and 4 (18.2%) had NR. 14 patients with tubular, IVUS showed 3 (21.4%) had IMT and 11 (78.6%) had NR. No difference in age of onset, gender, BMI, initial BP levels were found between IMT and NR subtypes. However, hypertension cure rates of short-term (48 h after angioplasty) (76.2% vs. 26.7%, p = 0.004) and long-term (1-6years) (90.5% vs. 20.0%, p < 0.001) were higher in patients with IMT than in those with NR subtype. In present study, we described a new classification of focal renal artery FMD into IMT or NR subtype based on IVUS. Renal FMD Patients with IMT subtype were more likely to achieve cure of hypertension. We investigated whether using an IVUS would provide additional insights in the hypertensive patients with focal renal artery FMD. A new classification of focal renal artery FMD into IMT or NR subtype based on IVUS was described. Renal FMD Patients with IMT subtype were more likely to achieve cure of hypertension.

Prevalence and clinical characteristics of renovascular hypertension associated with fibromuscular dysplasia in China.

OBJECTIVES: The aim of this study was to investigate the clinical characteristics of renal artery fibromuscular dysplasia (FMD) in patients in China and identify the cure rate of hypertension after angioplasty. METHODS: Consecutive hypertensive patients with renal artery stenosis caused by FMD who underwent catheter-based angiography, and were followed at two Chinese referral centres, were retrospectively analysed. All patients underwent a detailed investigation, including demographic characteristics, clinical characteristics, biochemical sampling, Doppler ultrasonography of carotid arteries, magnetic resonance angiography (MRA) of the intracranial artery, and CTA or MRA of the abdominal artery and catheter-based renal angiography. Patients were routinely followed up at 1 month, 6 months and every year after the procedure. RESULTS: Among 245 study participants, with a mean diagnosed age of 26.9 ±â€Š9.9 years, 137 (55.9%) were women, and 38 (15.5%) were children. All patients were diagnosed with hypertension at a mean age of 23.4 ±â€Š8.4 years. There were 73.5% focal and 15.2% multivessel cases. Aneurysms, arterial dissections and total occlusions were found in 21.6, 4.1 and 12.2% of patients, respectively. Patients with multifocal FMD were older (26.0 vs. 23.7 years, P  = 0.021) and more often female (70.8 vs. 50.6%, P  = 0.004). Among children with renal FMD, 55.2% were men, and 86.8% were focal. After a median follow-up of 7.0 years, multifocal FMD had a higher cure rate of hypertension than focal FMD after revascularization (71.7 vs. 55.8%, P  = 0.032). CONCLUSION: In a cohort of mostly young Chinese patients, the prevalence of hypertension associated with renal FMD is similar in both sexes. Focal FMDs were more frequent than the multifocal ones and, after angioplasty, were associated with a worse blood pressure outcome.

Microplastics extraction from wastewater treatment plants: Two-step digestion pre-treatment and application.

As the gathering place of urban wastewater, wastewater treatment plants (WWTPs) are indispensable for removing microplastics (MPs), one of the emerging contaminants of great concern, from cities into the natural environment. A reliable and efficient extraction method for MPs, especially in organic-rich matrices, such as sludge samples, is the basis for studying MPs contamination, while it is still lacking. The digestion process, which requires further optimisation, is the most important step during extraction. In this study, we developed and optimised a two-step digestion process to extract MPs and proposed a recommended dosage of digestion reagents based on the mixed liquid volatile suspended solids (MLVSS) level of the sample. Successive addition of 30% H2O2 + 1 M HNO3 (v:v = 1:1, T = 60 °C, t = 5 h + 5 h) could efficiently extract MPs from sludge samples (over 90%), and the recommended dosage of digestion reagent was 100 ml 30% H2O2+100 ml 1 M HNO3 with the sample MLVSS lower than approximately 0.43 g. This new method was also applied to examine the characteristics of MPs in two typical WWTPs (anaerobic-anoxic-oxic and biofilter processes) in Shenzhen. The concentrations of MPs in the influent, effluent and dewatered sludge were approximately 114.00 n/L, 6.00 n/L, and 126.00 n/g (dry weight) in WWTP A, whereas 404.00 n/L, 22.00 n/L, and 204.00 n/g (dry weight) in WWTP B, respectively. Rayon and polyester were the dominant polymers in both the WWTPs. Fibers accounted for the largest proportion of the influent and effluent. Sizes between 0.20-0.50 mm were most detected. This study provides a new and efficient reference method to extract MPs from WWTPs samples, especially sludge sample, with less MPs loss and more beneficial to subsequent identification.

Divergent BRAF Inhibitor Resistance Mechanisms Revealed through Epigenetic Mapping.

Although tremendous progress has been made in targeted and immune-based treatments for advanced melanoma, there remains a substantial therapeutic failure rate. For patients with BRAF(V600)-mutant melanomas, resistance to BRAF inhibitors remains a significant survival hurdle. Although multiple compensatory mechanisms to bypass BRAF blockade have been discovered, the epigenetic patterns are still poorly characterized. In this report, we generated eight matched pairs of vemurafenib-sensitive/-resistant melanoma lines and subjected these to concurrent RNA-sequencing and H3K27ac chromatin immunoprecipitation sequencing analysis. Globally, we identified two classes of epigenetic profiles that correlate with resistance. Class 1 resistance involves fewer RNA expression alterations accompanied by fewer enhancer mark changes with H3K27ac. Class 2 resistance shows widespread alterations in transcription and enhancer profiles, which converge on epithelial‒mesenchymal transition and hypoxia-related pathways. We also observed significant and dynamic changes in superenhancers that underpin these transcriptomic patterns. We subsequently verified the two-class structure in pre-BRAF inhibitors and postrelapse human melanoma specimens. Our findings reveal a broad and underappreciated spectrum of epigenetic plasticity during acquired BRAF inhibitor resistance.

Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα.

The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates. In the current study, we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARα protein to explore a potential therapeutic approach for this variant APL. We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents. However, mild hyperthermia (42 °C) rapidly destabilized the ZBTB16/RARα fusion protein expressed in HeLa, 293T, and OCI-AML3 cells, followed by robust ubiquitination and proteasomal degradation. In contrast, hyperthermia did not affect the normal (i.e., unfused) ZBTB16 and RARα proteins, suggesting a specific thermal sensitivity of the ZBTB16/RARα fusion protein. Importantly, we found that the destabilization of ZBTB16/RARα was the initial step for oncogenic fusion protein degradation by hyperthermia, which could be blocked by deletion of nuclear receptor corepressor (NCoR) binding sites or knockdown of NCoRs. Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.

Case report: Recurrence of hypertension after renal artery angioplasty due to the progression of focal renal fibromuscular dysplasia.

Whether fibromuscular dysplasia (FMD) is a progressive disease, remains unclear. We reported a case of focal renal artery FMD that slowly progressed to a branching artery over a few years after the angioplasty without in-stent restenosis, which reconfirms that focal FMD is progressive and that such progression may be segmental. Stenting may be an option for young, risk factor-free patients with focal FMD.

Regulation and roles of FOXK2 in cancer.

Forkhead box K2 (FOXK2) is a member of the forkhead box transcription factor family that contains an evolutionarily conserved winged-helix DNA-binding domain. Recently, an increasing number of studies have demonstrated that FOXK2 plays an important role in the transcriptional regulation of cancer. Here, we provide an overview of the mechanisms underlying the regulation of FOXK2 expression and function and discuss the roles of FOXK2 in tumor pathogenesis. Additionally, we evaluated the prognostic value of FOXK2 expression in patients with various cancers. This review presents an overview of the different roles of FOXK2 in tumorigenesis and will help inform the design of experimental studies involving FOXK2. Ultimately, the information presented here will help enhance the therapeutic potential of FOXK2 as a cancer target.

The Role of Urinary Extracellular Vesicles Sodium Chloride Cotransporter in Subtyping Primary Aldosteronism.

Background: Adrenal venous sampling (AVS) is recognized as the gold standard for subtyping primary aldosteronism (PA), but its invasive nature and technical challenges limit its availability. A recent study reported that sodium chloride cotransporter (NCC) in urinary extracellular vesicles (uEVs) is a promising marker for assessing the biological activity of aldosterone and can be treated as a potential biomarker of PA. The current study was conducted to verify the hypothesis that the expression of NCC and its phosphorylated form (pNCC) in uEVs are different in various subtypes and genotypes of PA and can be used to select AVS candidates. Methods: A total of 50 patients with PA were enrolled in the study. Urinary extracellular vesicles (uEVs) were isolated from spot urine samples using ultracentrifugation. NCC and pNCC expressions were tested in patients diagnosed with PA who underwent AVS. Sanger sequencing of KCNJ5 was performed on DNA extracted from adrenal adenoma. Results: pNCC (1.89 folds, P<.0001) and NCC (1.82 folds, P=0.0002) was more abundant in the uEVs in the high lateralization index (h-LI, ≥ 4) group than in the low LI (l-LI, < 4) group. Carriers of the somatic KCNJ5 mutations, compared with non-carriers, had more abundant pNCC expression (2.16 folds, P=0.0039). Positive correlation between pNCC abundance and plasma aldosterone level was found in this study (R = 0.1220, P = 0.0129). Conclusions: The expression of pNCC in uEVs in patients with PA with various subtypes and genotypes was different. It can be used as biomarker of AVS for PA subtyping.

Effect of Two-Stage Cooling on the Microstructure and Tribological Properties of Steel-Copper Bimetals.

In this paper, the solid-liquid composite method is used to prepare the steel-copper bimetal sample through two-stage cooling process (forced air cooling and oil cooling). The relationship between the different microstructures and friction properties of the bimetal copper layer is clarified. The results show that: the friction and wear parameters are 250 N, the speed is 1500 r/min (3.86 m/s), the friction coefficient fluctuates in the range of 0.06-0.1, and the lowest point is 0.06 at 700 °C. The microstructure of the copper layer was α-Cu, δ, Cu3P, and Pb phases, and Pb was free between α-Cu dendrites. When the solidification temperature is 900 °C, the secondary dendrite of α-Cu develops. With the decrease temperature, the growth of primary and secondary dendrites gradually tends to balance at 700 °C. During the wear process, Pb forms a self-lubricating film uniformly distributed on the surface of α-Cu, and the Cu3P and δ phases are distributed in the wear mark to increase α-Cu wear resistance.

NRP2, a potential biomarker for oral squamous cell carcinoma.

BACKGROUND: Neuropilin-2 (NRP2) is a single chain transmembrane glycoprotein that acts as a co-receptor of VEGF and is related to the pathogenesis of various tumors closely. However, the clinical significance of NRP2 in oral squamous cell carcinoma (OSCC) is unclear. PURPOSE: The objective of this study was to investigate the role of NRP2 in the pathogenesis of OSCC and explore the associated mechanisms. MATERIALS AND METHODS: GEPIA (gene expression profiling interactive analysis) was used to analyze the expression of NRP2 in OSCC. Immunohistochemistry and RT-qPCR were used to detect NRP2 expression in 80 OSCC samples. The clinical correlations and prognostic significance of NRP2 expression were evaluated. In addition, the biological functions of OSCC cells transfected with shNRP2 were evaluated. The expression levels of ß-catenin, C-myc, cyclin D1, and MMP-2 in Wnt/ß-catenin signaling pathway were assessed by RT-qPCR after inhibiting the expression of NRP2 in SCC-25 cell line. RESULTS: Analysis of cases using GEPIA revealed that NRP2 was substantially upregulated in OSCC. NRP2 expression was also significantly higher in our OSCC samples than in the controls. Elevated expression of NRP2 was correlated with lymph node metastasis (P<0.01) and distant metastasis (P<0.05) in OSCC patients, and high NRP2 levels, lymph node metastasis, and distant metastasis were associated with poor prognosis (Kaplan-Meier analysis; P<0.05). Univariate and multivariate Cox analysis showed that lymph node metastasis, distant metastasis, and NRP2 expression were independent risk factors for overall survival (OS) and disease-free survival (DFS) in OSCC patients (P<0.05). Furthermore, the proliferation, migration, and invasion of OSCC cells were inhibited by shNRP2. Following inhibiting of NRP2 expression in the SCC-25 cell line, the expression levels of ß-catenin, C-myc, cyclin D1, and MMP-2 were reduced (P<0.05). CONCLUSION: This study shows that NRP2 functions as a tumor promoter gene in OSCC by affecting the proliferation, migration, and invasion of OSCC cells and downregulating the Wnt/ß-catenin pathway. These results highlight the potential role for NRP2 as a clinical diagnostic marker.

Comprehensive Analysis of the Expression Characteristics of the Enhancer of the Zeste Homolog 2 Gene in Pan-Cancer.

Although more and more studies have shown that EZH2 was closely related to human cancer, no pan-cancer analysis is available. Therefore, we summarized and analyzed the potential carcinogenic effect of EZH2 for the first time based on TCGA (cancer genome map) datasets. EZH2 is expressed highly in most tumors and there is a significant correlation between the EZH2 expression and the prognosis of patients. We observed the increased phosphorylation levels of T487 in breast cancer, colon cancer, UCEC, and LUAD. The expression of EZH2 was associated with the CD8+, tregs, macrophage, and cancer-associated fibroblast infiltration in some tumors. In addition, the cell cycle and cellular biology were involved in the functional mechanisms of EZH2. Our study summarized and analyzed the carcinogenic effect of EZH2 in different tumors comprehensively and provided a theoretical basis for targeting EZH2 therapy.

Targeting Ubiquitin-Specific Protease 7 (USP7) in Cancer: A New Insight to Overcome Drug Resistance.

Chemoresistance is one of the leading causes for the failure of tumor treatment. Hence, it is necessary to study further and understand the potential mechanisms of tumor resistance to design and develop novel anti-tumor drugs. Post-translational modifications are critical for proteins' function under physiological and pathological conditions, among which ubiquitination is the most common one. The protein degradation process mediated by the ubiquitin-proteasome system is the most well-known function of ubiquitination modification. However, ubiquitination also participates in the regulation of many other biological processes, such as protein trafficking and protein-protein interaction. A group of proteins named deubiquitinases can hydrolyze the isopeptide bond and disassemble the ubiquitin-protein conjugates, thus preventing substrate proteins form degradation or other outcomes. Ubiquitin-specific protease 7 (USP7) is one of the most extensively studied deubiquitinases. USP7 exhibits a high expression signature in various malignant tumors, and increased USP7 expression often indicates the poor tumor prognosis, suggesting that USP7 is a marker of tumor prognosis and a potential drug target for anti-tumor therapy. In this review, we first discussed the structure and function of USP7. Further, we summarized the underlying mechanisms by which tumor cells develop resistance to anti-tumor therapies, provided theoretical support for targeting USP7 to overcome drug resistance, and some inspiration for the design and development of USP7 inhibitors.

MicroRNA­198 suppresses tumour growth and metastasis in oral squamous cell carcinoma by targeting CDK4.

MicroRNAs (miRNAs/miR) often contribute to the progression of oral squamous cell carcinoma (OSCC) via the regulation of mRNA. The present study aimed to investigate the role of miR­198 in OSCC pathogenesis and explore the underlying mechanism. Reverse transcription­quantitative (RT­q)PCR was performed to determine miR­198 expression in OSCC tissues and cell lines, and univariate and multivariate analyses were applied to evaluate the survival of patients with OSCC. The effects of miR­198 on OSCC cell lines were studied in vitro and in vivo. A set of epithelial­mesenchymal transition (EMT) markers were detected to determine whether miR­198 was involved in EMT. Lastly, using luciferase assays, a novel target of miR­198 was identified and the effect of the new target gene of miR­198 on cell proliferation and invasion was also studied. It was identified that miR­198 expression was decreased in OSCC tissues and cell lines, and low expression of miR­198 was associated with poor overall survival and disease­free survival. Overexpression of miR­198 appeared to significantly inhibit the proliferation, invasion and EMT of OSCC cells. Moreover, the luciferase assay results showed that miR­198 interacted with cyclin­dependent kinase 4 (CDK4) by directly targeting the miRNA­binding site in the CDK4 sequence, and RT­qPCR results showed that CDK4 expression was increased in OSCC tissues and cell lines. In addition, transfection of small interfering RNA against CDK4 in OSCC cells showed similar inhibitory effects on cell proliferation, invasion and EMT, whereas CDK4 overexpression in OSCC cells partially reversed the inhibitory effects of the miR­198 mimic. The present results indicated that miR­198 suppressed OSCC tumour growth and metastasis by directly targeting CDK4 expression. Thus, miR­198 may be a potential therapeutic target in the treatment of OSCC.

The prevalence of masked hypertension in relation to cigarette smoking in a Chinese male population.

BACKGROUND: Smokers may smoke cigarettes during ambulatory or home blood pressure (BP) monitoring but not clinic measurement. We investigated the prevalence of masked hypertension in relation to cigarette smoking in Chinese outpatients enrolled in a multicenter registry. METHODS: Our study included 1646 men [494 (30.0%) current smokers]. We defined masked hypertension as a normal clinic SBP/DBP (<140/90 mmHg) and elevated daytime (≥135/85 mmHg) or night-time (≥120/70 mmHg) ambulatory or morning or evening home SBP/DBP (≥135/85 mmHg). RESULTS: In all men, multiple logistic regression showed that current cigarette smoking was significantly associated with daytime [prevalence 18.7%, odds ratio (OR) 1.69, 95% confidence interval 1.27-2.25, P = 0.0003] but not night-time (prevalence 27.1%, P = 0.32) ambulatory masked hypertension and associated with evening (prevalence 14.6%, OR 1.81, confidence interval 1.33-2.47, P = 0.0002) but not morning (prevalence 17.6%, P = 0.29) home masked hypertension. The associations were more pronounced for heavy smoking (≥20 cigarettes/day) relative to never smoking for both masked daytime ambulatory (OR 1.97, P = 0.001) and evening home hypertension (OR 2.40, P < 0.0001) or in patients over 55 years of age (P for interaction in relation to daytime ambulatory masked hypertension = 0.005). In men with clinic normotension (n = 742), the associations were also significant (P < 0.01), particularly in those with a normal to high-normal clinic BP (n = 619, P < 0.04). CONCLUSION: Cigarette smoking was associated with increased odds of masked daytime ambulatory and evening home hypertension, especially in heavy smoking or older men.

Hypoxia and HIF-1α Regulate Collagen Production in Keloids.

Keloids are reactive or spontaneous fibroproliferative dermal tumors characterized by the exaggerated and uncontrolled accumulation of extracellular collagen. Current approaches to mitigate keloidogenesis are largely procedural in nature. However, a better understanding of its biological drivers may lead to novel targeted treatments for keloids. Through whole-genome expression analysis, we found that an HIF-1α transcriptional footprint is preferentially upregulated (activation score = 2.024; P = 1.05E-19) in keloid fibroblasts compared with normal dermal fibroblasts. We verified that HIF-1α protein is more strongly expressed in keloid specimens compared with normal skin (P = 0.035) and that hypoxia (1% O2) leads to increased collagen, especially in the extracellular compartment. Collagen levels were reduced uniformly by selective HIF-1α inhibitor CAY10585. Our results indicate that collagen secretion may be intimately linked to a hypoxic microenvironment within keloid tumors and that HIF-1α blockade could be a novel avenue of treatment for these tumors.

BAP18 is involved in upregulation of CCND1/2 transcription to promote cell growth in oral squamous cell carcinoma.

BACKGROUND: As a reader of histone H3K4me3, BPTF associated protein of 18 kDa (BAP18) is involved in modulation of androgen receptor action in prostate cancer. However, the function of BAP18 on oral squamous cell carcinoma (OSCC) and its molecular mechanism remains to be elusive. METHODS: OSCC-derived cell lines carrying silenced BAP18 were established by Lentiviral infection. Quantitative PCR (qPCR), western blot, and ChIP assay were performed to detect gene transcription regulation and the possible mechanism. Colony formation, cell growth curve and xenograft tumor experiments were performed to examine cell growth and proliferation. FINDINGS: Our study demonstrated that BAP18 was highly expressed in OSCC samples compared with that in benign. BAP18 depletion obviously influenced the expression of a series of genes, including cell cycle-related genes. We thus provided the evidence to demonstrate that BAP18 depletion significantly decreases CCND1 and CCND2 (CCND1/2) transcription. In addition, BAP18 is recruited to the promoter regions of CCND1/2, thereby facilitating the recruitment of the core subunits of MLL1 complex to the same regions, to increase histone H3K4me3 levels. Furthermore, BAP18 depletion delayed G1-S phase transition and inhibited cell growth in OSCC-derived cell lines. INTERPRETATION: This study suggests that BAP18 is involved in modulation of CCND1/2 transcription and promotes OSCC progression. BAP18 could be a potential target for OSCC treatment and diagnosis. FUND: This work was funded by National Natural Science Foundation of China (31871286, 81872015, 31701102, 81702800, 81902889), Foundation for Special Professor of Liaoning Province, and Supported project for young technological innovation-talents in Shenyang (No. RC170541).

Alteration of CTCF-associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis.

Aberrant activation of the TAL1 is associated with up to 60% of T-ALL cases and is involved in CTCF-mediated genome organization within the TAL1 locus, suggesting that CTCF boundary plays a pathogenic role in T-ALL. Here, we show that -31-Kb CTCF binding site (-31CBS) serves as chromatin boundary that defines topologically associating domain (TAD) and enhancer/promoter interaction required for TAL1 activation. Deleted or inverted -31CBS impairs TAL1 expression in a context-dependent manner. Deletion of -31CBS reduces chromatin accessibility and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter-1 leading to inhibition of TAL1 expression in erythroid cells, but not T-ALL cells. However, in TAL1-expressing T-ALL cells, the leukemia-prone TAL1 promoter-IV specifically interacts with the +19 stem cell enhancer located 19 Kb downstream of TAL1 and this interaction is disrupted by the -31CBS inversion in T-ALL cells. Inversion of -31CBS in Jurkat cells alters chromatin accessibility, histone modifications and CTCF-mediated TAD leading to inhibition of TAL1 expression and TAL1-driven leukemogenesis. Thus, our data reveal that -31CBS acts as critical regulator to define +19-enhancer and the leukemic prone promoter IV interaction for TAL1 activation in T-ALL. Manipulation of CTCF boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.