Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity.

Regulatory T (Treg) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving Treg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral Treg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral Treg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor Treg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor Treg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral Treg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor Treg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor Treg cells without affecting systemic immune homeostasis.

H3K36 methyltransferase NSD1 is essential for normal B1 and B2 cell development and germinal center formation.

B cells, which consist of two well-defined populations: B1 and B2 cells, which can produce antibodies that are essential for host protection against infections, through virus neutralization, opsonization and antibody-dependent cellular cytotoxicity. Epigenetic modifications, such as DNA methylation and histone modification could regulate immune cell differentiation and functions. In this study, we found a significant reduction of GC response in the B cell specific knockout of H3K36 methyltransferase NSD1 (Mb1-Cre+ NSD1fl/fl, NSD1B KO) mice compared with the wildtype control (Mb1-Cre+ NSD1+/+, NSD1B WT). We also demonstrated reduced production of high-affinity antibody, but increased production of low-affinity antibody in the NSD1B KO mice. Further analysis revealed that loss of NSD1 promoted the development of B1 cells by increasing the expression of Rap1b and Arid3a. In conclusion, our data suggest that NSD1 plays an important role in regulation the development of B1 and B2 cells, and the process of germinal center formation and high-affinity antibody production.

Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis.

Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.

Histone methyltransferase Nsd2 ensures maternal-fetal immune tolerance by promoting regulatory T-cell recruitment.

Regulatory T cells (Tregs) are fundamentally important for maintaining systemic immune homeostasis and are also required for immune tolerance at the maternal-fetal interface during pregnancy. Recent studies have suggested that epigenetic regulation is critically involved in Treg development and function. However, the role of H3K36me has not yet been investigated. Here, we found that the H3K36me2 methyltransferase Nsd2 was highly expressed in Tregs. Although loss of Nsd2 did not impair systemic Treg development or function, the level of Tregs at the maternal-fetal interface was significantly decreased in pregnant Nsd2 conditional knockout mice. Consequently, maternal-fetal immune tolerance was disrupted in the absence of Nsd2 in Tregs, and the pregnant mice showed severe fetal loss. Mechanistically, Nsd2 was found to upregulate CXCR4 expression via H3K36me2 modification to promote Treg cell recruitment into the decidua and suppress the anti-fetal immune response. Overall, our data identified Nsd2 as a critical epigenetic regulator of Treg recruitment for maternal-fetal tolerance.

Simplified Method of Microcontact Force Measurement by Using Micropressure Sensor.

Microcontact force measurement is widely applied in micro/nano manufacturing, medicine and microelectromechanical systems. Most microcontact force measurements are performed by using mass comparators, nano-indenter and precision electronic balance, and weighing sensors. However, these instruments have a complex structure and high cost. Nevertheless, the rapid development of microsensor technology provides a new, simple and low-cost approach for microcontact force measurement. In this study, we present a method of microcontact force measurement by using micropressure sensors and study the relationship amongst the microcontact force, output voltage and contact position of the sensor. We use a microcapacitance pressure sensor as an example, then we perform a simulation calculation and construct a microcontact force experiment system to verify the simulation results. The experimental and simulation results are consistent. In addition, an equation that describes the relationship amongst the microcontact force, output voltage and contact position of the sensor is obtained. Based on this simple and low-cost method, we build a micro-manipulation system, which indicates that the micropressure sensors can be used to measure microcontact force in various applications easily and cost-effectively. Furthermore, it is considerably relevant to research and application in this field.

The occurrence and treatment of hemophagocytic lymphohistiocytosis caused by multiple factors: a case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH) is a high-fatality disease caused by hereditary or acquired immune dysfunction, and is characterized by pathological inflammatory response. Primary HLH (pHLH) has hereditary genetic defects, and secondary HLH (sHLH) is caused by a variety of underlying diseases. Here, we report the case of a patient with aggressive natural killer cell leukemia and HLH-related gene defects who achieved long-term survival after treatment. A 20-year-old man presented to our hospital with symptoms of fever and fatigue. Investigations revealed splenomegaly, cytopenia, hyperferritinemia, hypofibrinogenemia, elevated levels of soluble CD25 (sCD25), and hemophagocytosis in bone marrow. Bone marrow flow cytometry showed 23.4% abnormal natural killer cells, the cells were CD2, CD7, CD16, CD94, NKG2A positive, met the diagnosis of aggressive NK-Cell leukemia. Investigation of the patient's pedigree revealed that mutations of pHLH-related genes (LYST and UNC13D) were inherited from his father and mother, but neither of the parents had the disease. The patient received hematopoietic stem-cell transplantation (HSCT), after which he achieved complete remission. As of 2020-10-19, the patient's survival has exceeded 3 years, and he has returned to his normal life. A variety of factors contribute to the onset of HLH, and this case gives greater insight into the etiology of HLH. Allogeneic HSCT is a key treatment for HLH patients with underlying genetic mutations.

Adipose Mesenchymal Stem Cell-Derived Exosomal microRNA-1236 Reduces Resistance of Breast Cancer Cells to Cisplatin by Suppressing SLC9A1 and the Wnt/ß-Catenin Signaling.

BACKGROUND: Emerging evidence has noted the versatile functions of mesenchymal stem cell-derived exosomes (MSC-Exos) in cancer control. This work aims to probe to function of adipose MSC-Exos (adMSC-Exos) in drug-resistance of breast cancer (BC) cells to cisplatin (DDP) and the molecules involved. METHODS: Parental and DDP-resistant BC cell lines MCF-7 and MDA-MB-231 were used. All cells were pre-treated with adMSC-Exos. Then, the viability and apoptosis of cells after DDP treatment were determined. Differentially expressed miRNAs after adMSC-exo treatment were screened out. Rescue experiments were conducted by pre-transfecting miR-1236 inhibitor into adMSCs, and the role of miR-1236 in DDP sensitivity was determined. Targeting mRNAs of miR-1236 were predicted by bioinformatics analysis. Altered SLC9A1 expression was administrated to evaluate its function in DDP resistance. RESULTS: The adMSC-Exos notably increased the sensitivity of either parental or DDP-resistant BC cells to DDP. SLC9A1 was notably highly expressed in DDP-resistant cells but inhibited following adMSC-exo administration. Importantly, miR-1236, which could directly bind to SLC9A1 and suppress its expression, was confirmed as an enriched miRNA in adMSC-Exos. Either inhibition of miR-1236 or upregulation of SLC9A1 blocked the pro-sensitize roles of adMSC-Exos. In addition, the Wnt/ß-catenin pathway activity was suppressed by adMSC-Exos but recovered by SLC9A1. CONCLUSION: This study evidenced that adMSC-Exos carry miR-1236 to increase sensitivity of BC cells to DDP with the involvement of SLC9A1 downregulation and Wnt/ß-catenin inactivation. This finding may offer novel insights into treatment for drug-resistant BC.

Association between TERT gene polymorphisms and acute myeloid leukemia susceptibility in a Chinese population: a case-control study.

BACKGROUND: The aim of this study was to investigate the association between telomerase reverse transcriptase (TERT) gene polymorphisms and acute myeloid leukemia (AML) susceptibility in a Chinese Han population. METHODS: A total of 102 AML patients and 108 healthy controls were enrolled in this case-control study. TERT gene rs2853669 and rs2736100 polymorphisms were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Chi-square test was applied to compare polymorphism distributions between case and control groups. The strength of the association between TERT gene polymorphisms and AML susceptibility was evaluated utilizing odds ratio (OR) with corresponding 95% confidence interval (CI). RESULTS: CC genotype and C allele of rs2736100 polymorphism were more frequent in AML patients (P < 0.05), and individuals carrying CC genotype showed higher risk of suffering from AML (OR = 2.632, 95% CI 1.129-6.133). But for rs2853669 polymorphism, no significant differences were detected in either genotype or allele distributions between groups (P > 0.05). CONCLUSIONS: This study suggested a positive association between TERT gene rs2736100 polymorphism and AML susceptibility in Chinese Han population.

Association of ERCC2 Gene Polymorphisms with Susceptibility to Diffuse Large B-Cell Lymphoma.

BACKGROUND The objective of this study was to detect the association between ERCC excision repair 2, TFIIH core complex helicase subunit (ERCC2) gene polymorphisms and diffuse large B-cell lymphoma (DLBCL) susceptibility. MATERIAL AND METHODS This study used a case-control design. ERCC2 gene rs1799793 (Asp312Asn) and rs13181 (Lys751Gln) polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) both in DLBCL patients and healthy controls. The association between ERCC2 gene polymorphisms and DLBCL risk was assessed by χ² test. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were used to address the association strength. Subgroup analyses were also performed to investigate the genetic effects of ERCC2 polymorphisms on clinical characteristics of DLBCL patients. RESULTS A significant association was discovered between the rs1799793 A allele and increased DLBCL risk (P=0.031, OR=1.928, 95% CI=1.052-3.534). The C allele of rs13181 was obviously associated with elevated DLBCL susceptibility (P=0.047, OR=1.820, 95% CI=1.002-3.305). The subgroup analysis demonstrated that rs1799793 and rs13181 polymorphisms had no relationship with serum lactate dehydrogenase level, nidus number, B-symptoms, Ann Arbor stages, or immunological types in DLBCL cases (P>0.05 for all). CONCLUSIONS Minor allele carriers of ERCC2 gene rs1799793 (Asp312Asn) and rs13181 (Lys751Gln) polymorphisms had higher susceptibility to DLBCL.