BRG1 promotes progression of B-cell acute lymphoblastic leukemia by disrupting PPP2R1A transcription.

Despite advancements in chemotherapy and the availability of novel therapies, the outcome of adult patients with B-cell acute lymphoblastic leukemia (B-ALL) remains unsatisfactory. Therefore, it is necessary to understand the molecular mechanisms underlying the progression of B-ALL. Brahma-related gene 1 (BRG1) is a poor prognostic factor for multiple cancers. Here, the expression of BRG1 was found to be higher in patients with B-ALL, irrespective of the molecular subtype, than in healthy individuals, and its overexpression was associated with a poor prognosis. Upregulation of BRG1 accelerated cell cycle progression into the S phase, resulting in increased cell proliferation, whereas its downregulation facilitated the apoptosis of B-ALL cells. Mechanistically, BRG1 occupies the transcriptional activation site of PPP2R1A, thereby inhibiting its expression and activating the PI3K/AKT signaling pathway to regulate the proto-oncogenes c-Myc and BCL-2. Consistently, silencing of BRG1 and administration of PFI-3 (a specific inhibitor targeting BRG1) significantly inhibited the progression of leukemia and effectively prolonged survival in cell-derived xenograft mouse models of B-ALL. Altogether, this study demonstrates that BRG1-induced overactivation of the PPP2R1A/PI3K/AKT signaling pathway plays an important role in promoting the progression of B-ALL. Therefore, targeting BRG1 represents a promising strategy for the treatment of B-ALL in adults.

Overexpression of Nrf2 in bone marrow mesenchymal stem cells promotes B-cell acute lymphoblastic leukemia cells invasion and extramedullary organ infiltration through stimulation of the SDF-1/CXCR4 axis.

Background: Tumor microenvironment (TME) represents the key factor inducing leukemia development. As stromal cells within the leukemia microenvironment, Bone Marrow Mesenchymal Stem Cells (BM-MSCs) can trigger leukemia progression under certain conditions. As a critical transcription factor, nuclear factor erythroid related factor 2 (Nrf2) can modulate antioxidant response and antioxidant enzyme gene expression, and prevent various oxidative changes. We previously identified a novel mechanism by which Nrf2 promotes leukemia resistance, providing a potential therapeutic target for the treatment of drug-resistant/refractory leukemias. However, the role of Nrf2 in BM-MSCs from B-cell acute lymphoblastic leukemia (B-ALL) patients has not been clearly reported. The present work focused on investigating the effect of Nrf2 overexpression within MSCs on leukemia cell invasion, extramedullary infiltration and proliferation as well as its downstream pathway. Methods: Through clinical sample detection, in vitro cell experiments and in vivo animal experiments, the role of Nrf2 within MSCs within adult B-ALL cell migration and invasion and its potential molecular mechanism was explored through transcriptome sequencing analysis, RT-PCR, Western blot, cell migration, cell invasion, lentivirus transfection and other experiments. Results: Nrf2 was highly expressed in BM-MSCs from patients with B-ALL as well as in BM-MSCs co-cultured with leukemia cells. Overexpression of Nrf2 within MSCs significantly promoted leukemia cell migration, invasion and proliferation. The extramedullary organ infiltration rate in B-ALL model mice receiving the combined infusion of both cell types dramatically increased relative to that of leukemia cells alone, accompanied by the significantly shortened survival time. Mechanism study found that Nrf2 overexpression within MSCs promoted PI3K-AKT/ERK1/2 phosphorylation in the downstream pathway by activating SDF-1/CXCR4 axis, ultimately leading to extramedullary infiltration of leukemia cells. Conclusion: High Nrf2 expression with in MSCs enhances leukemia cell invasion and migration, which then accelerates infiltration in leukemic extramedullary organs. Targeting Nrf2 or inhibiting its downstream signal molecules may be the effective interventions for B-ALL patients treatment.

Dual roles of CD11b+CD33+HLA-DR-/lowCD14- myeloid-derived suppressor cells with a granulocytic morphology following allogeneic hematopoietic stem cell transplantation: from inflammation promoters to immune suppressors within 90 days.

Introduction: Granulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions. Methods: G-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions. Results: G-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes. Conclusion: Our findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.

Identification of a novel monocyte/macrophage-related gene signature for predicting survival and immune response in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological tumor with poor immunotherapy effect. This study was to develop a monocyte/macrophage-related prognostic risk score (MMrisk) and identify new therapeutic biomarkers for AML. We utilized differentially expressed genes (DEGs) in combination with single-cell RNA sequencing to identify monocyte/macrophage-related genes (MMGs). Eight genes were selected for the construction of a MMrisk model using univariate Cox regression analysis and LASSO regression analysis. We then validated the MMrisk on two GEO datasets. Lastly, we investigated the immunologic characteristics and advantages of immunotherapy and potential targeted drugs for MMrisk groups. Our study identified that the MMrisk is composed of eight MMGs, including HOPX, CSTB, MAP3K1, LGALS1, CFD, MXD1, CASP1 and BCL2A1. The low MMrisk group survived longer than high MMrisk group (P < 0.001). The high MMrisk group was positively correlated with B cells, plasma cells, CD4 memory cells, Mast cells, CAFs, monocytes, M2 macrophages, Endothelial, tumor mutation, and most immune checkpoints (PD1, Tim-3, CTLA4, LAG3). Furthermore, drug sensitivity analysis showed that AZD.2281, Axitinib, AUY922, ABT.888, and ATRA were effective in high-risk MM patients. Our research shows that MMrisk is a potential biomarker which is helpful to identify the molecular characteristics of AML immunology.

Targeting histone deacetylase 1 (HDAC1) in the bone marrow stromal cells revers imatinib resistance by modulating IL-6 in Ph + acute lymphoblastic leukemia.

Bone marrow stromal cells (BMSCs) can promote the growth of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Histone deacetylases (HDACs) play essential roles in the proliferation and apoptosis resistance of Ph + ALL cells. In our previous study, inhibiting histone deacetylase 1 (HDAC1) decreases the proliferation of Ph + ALL cells. However, little is known regarding how HDAC1 in BMSCs of Ph + ALL patients affects the imatinib (IM) resistance. Therefore, the present work examined the roles of HDAC1 in BMSCs. Overexpression of HDAC1 was found in BMSCs of Ph + ALL patients with IM resistance. In addition, the Ph + ALL cell line SUP-B15 was co-cultured with BMSCs after lentivirus transfection for regulating HDAC1 expression. Knockdown of HDAC1 within BMSCs elevated the IM-mediated SUP-B15 cell apoptosis, while increasing HDAC1 expression had an opposite effect. IL-6 in BMSCs, which is an important factor for the microenvironment-associated chemoresistance, showed evident up-regulation in HDAC1-upregulated BMSCs and down-regulation in HDAC1-downregulated BMSCs. While recombinant IL-6 (rIL-6) can reversed the sensitivity of SUP-B15 cells to IM induced by downregulating HDAC1 expression in BMSCs. HDAC1 showed positive regulation on IL-6 transcription and secretion. Moreover, IL-6 secretion induced by HDAC1 in BMSCs might enhance IM resistance in Ph + ALL cells. With regard to the underlying molecular mechanism, NF-κB, an important signal responsible for IL-6 transcription in BMSCs, mediated the HDAC1-regulated IL-6 expression. Collectively, this study facilitated to develop HDAC1 inhibitors based not only the corresponding direct anti-Ph + ALL activity but also the regulation of bone marrow microenvironment.

Exploring pollutant joint effects in disease through interpretable machine learning.

Identifying the impact of pollutants on diseases is crucial. However, assessing the health risks posed by the interplay of multiple pollutants is challenging. This study introduces the concept of Pollutants Outcome Disease, integrating multidisciplinary knowledge and employing explainable artificial intelligence (AI) to explore the joint effects of industrial pollutants on diseases. Using lung cancer as a representative case study, an extreme gradient boosting predictive model that integrates meteorological, socio-economic, pollutants, and lung cancer statistical data is developed. The joint effects of industrial pollutants on lung cancer are identified and analyzed by employing the SHAP (Shapley Additive exPlanations) interpretable machine learning technique. Results reveal substantial spatial heterogeneity in emissions from CPG and ILC, highlighting pronounced nonlinear relationships among variables. The model yielded strong predictions (an R of 0.954, an RMSE of 4283, and an R2 of 0.911) and emphasized the impact of pollutant emission amounts on lung cancer responses. Diverse joint effects patterns were observed, varying in terms of patterns, regions (frequency), and the extent of antagonistic and synergistic effects among pollutants. The study provides a new perspective for exploring the joint effects of pollutants on diseases and demonstrates the potential of AI technology to assist scientific discovery.

S-Ketamine Improves Slow Wave Sleep and the Associated Changes in Serum Protein Among Gynecological Abdominal Surgery Patients: A Randomized Controlled Trial.

Purpose: This study aims to evaluate the effect of S-ketamine on slow wave sleep (SWS) and the related changes in serum protein in gynecological patients after open abdomen surgery. Methods: This was a randomized controlled trial. One hundred gynecological patients undergoing open abdomen surgery were randomized into an S-ketamine group (group S) or placebo group (0.9% saline; group C). During operation, patients in group S received adjuvant S-ketamine infusion (0.2 mg·kg-1·h-1) while those in group C received 0.9% saline. All patients were connected to patient-controlled intravenous analgesia (PCIA) pump in the end of the surgery and the patients in group S with an additional S-ketamine in PCIA pump. Polysomnogram (PSG) was monitored during the next night after surgery with PCIA pump. Blood samples were collected for proteomic analysis at 6:00 AM after PSG monitoring. The primary outcome was the percentage of SWS (also known as stage 3 non-rapid eye movement sleep, stage N3) on the next night after surgery, and the secondary outcome was subjective sleep quality, pain scores, and the changes in serum proteomics. Results: Complete polysomnogram recordings were obtained from 64 study participants (31 in group C and 33 in group S). The administration of S-ketamine infusion resulted in a significant increase in the percentage of SWS/N3 compared to the control group (group C, median (IQR [range]), 8.9 (6.3, 12.5); group S, median (IQR [range]), 15.6 (12.4, 18.8), P<0.001). However, subjective evaluations of sleep quality revealed no significant variances between the two groups. The protein affected by S-ketamine was primarily associated with posttranslational modification, protein turnover, carbohydrate transport, and metabolism. Conclusion: In patients undergoing open gynecological surgery, S-ketamine enhanced the percentage of objective sleep of SWS during the next night after surgery. Additionally, there were differences observed in serum protein levels between the two groups. Trial Registration: ChiCTR2200055180. Registered on 02/01/2022.

SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis.

Solute carrier family 25 member 51 (SLC25A51) was recently identified as the mammalian mitochondrial NAD+ transporter essential for mitochondria functions. However, the role of SLC25A51 in human disease, such as cancer, remains undefined. Here, we report that SLC25A51 is upregulated in multiple cancers, which promotes cancer cells proliferation. Loss of SLC25A51 elevates the mitochondrial proteins acetylation levels due to SIRT3 dysfunctions, leading to the impairment of P5CS enzymatic activity, which is the key enzyme in proline biogenesis, and the reduction in proline contents. Notably, we find fludarabine phosphate, an FDA-approved drug, is able to bind with and inhibit SLC25A51 functions, causing mitochondrial NAD+ decrease and proteins hyperacetylation, which could further synergize with aspirin to reinforce the anti-tumor efficacy. Our study reveals that SLC25A51 is an attractive anti-cancer target, and provides a novel drug combination of fludarabine phosphate with aspirin as a potential cancer therapy strategy.

CCDC134 facilitates T cell activation through the regulation of early T cell receptor signaling.

Modulation of surface T cell antigen receptor (TCR) expression is crucial for proper T cell development and maintenance of mature T cell function at steady state and upon stimulation. We previously determined that CCDC134 (coiled-coil domain containing 134), a cytokine-like molecule that served as a potential member of the γc cytokine family, contributes to antitumor responses by augmenting CD8+ T cell-mediated immunity. Here we show that T cell-specific deletion of Ccdc134 decreased peripheral mature CD4+ and CD8+ T cells, which resulted in impaired T cell homeostasis. Moreover, Ccdc134-deficient T cells exhibited an attenuated response to TCR stimulation in vitro, showing lower activation and proliferative capacity. This was further reflected in vivo, rendering mice refractory to T cell-mediated inflammatory and antitumor responses. More importantly, CCDC134 is associated with TCR signaling components, including CD3ϵ, and attenuated TCR signaling in Ccdc134-deficient T cells via altered CD3ϵ ubiquitination and degradation. Taken together, these findings suggest a role for CCDC134 as a positive regulator of TCR-proximal signaling and provide insight into the cell-intrinsic functional consequences of Ccdc134 deficiency in the attenuation of T cell-mediated inflammatory and antitumor responses.

Label-free serum proteomics for the identification of the putative biomarkers of postoperative pain in patients with gastric cancer.

Background: Individualized pain therapy conforms to the concept of precision medicine and contributes to adequate pain management after surgery. Preoperative biomarkers associated with postoperative pain may instruct anesthesiologists to improve personalized suitable analgesia. Therefore, it is essential to explore the association between preoperative proteins and postoperative acute pain using the proteomics platform. Methods: In this study, the 24 hours postoperative sufentanil consumption of 80 male patients with gastric cancer was ranked. Patients with sufentanil consumption in the lowest 12% were included in the sufentanil low consumption group, while patients with sufentanil consumption in the highest 12% were included in the sufentanil high consumption group. The secretion of serum proteins in both groups was analyzed using label-free proteomics technology. The results were validated by ELISA. Results: Proteomics identified 29 proteins that were significantly differentially expressed between groups. ELISA confirmed that secretion of TNC and IGFBP2 was down-regulated in the SLC group. The differential proteins were mainly extracellular and were involved in several terms, including calcium ion binding, laminin-1 binding, and so on. Pathway analysis showed that they were mainly enriched in focal adhesion and extracellular matrix-receptor interaction. The protein-protein interaction network analysis showed 22 proteins that interacted with other proteins. F13B had the strongest correlation with sufentanil consumption and its AUC value was 0.859. Conclusions: Several differential proteins are associated with postoperative acute pain and are involved in ECM-related processes, inflammation, and blood coagulation cascades. F13B may be a novel marker for postoperative acute pain. Our results may benefit postoperative pain management.

S-ketamine promotes postoperative recovery of gastrointestinal function and reduces postoperative pain in gynecological abdominal surgery patients: a randomized controlled trial.

BACKGROUND: This prospective randomized controlled study was designed to evaluate the effect of S-ketamine with sufentanil given intraoperatively and postoperatively on recovery of gastrointestinal (GI) function and postoperative pain in gynecological patients undergoing open abdomen surgery. METHODS: One hundred gynecological patients undergoing open abdomen surgery were randomized into an S-ketamine group (group S) or placebo group (0.9% saline; group C). Anesthesia was maintained with S-ketamine, sevoflurane, and remifentanil-propofol target-controlled infusion in group S and with sevoflurane and remifentanil-propofol target-controlled infusion in group C. All patients were connected to patient-controlled intravenous analgesia (PCIA) pump at the end of the surgery with sufentanil, ketorolac tromethamine, and tropisetron in group C and additional S-ketamine in group S. The primary outcome was the time of first postoperative flatus, and the secondary outcome was postoperative pain score of patients. Postoperative sufentanil consumption within the first postoperative 24 h and adverse events such as nausea and vomiting were recorded. RESULTS: The time of first postoperative flatus in group S was significantly shorter (mean ± SD, 50.3 ± 13.5 h) than that in group C (mean ± SD, 56.5 ± 14.3 h, p = 0.042). The patient's visual analog scale (VAS) pain score 24 h after surgery at rest was significantly lower in group S than in group C (p = 0.032). There were no differences in sufentanil consumption within the first postoperative 24 h, postoperative complications related to PCIA between the two groups. CONCLUSIONS: S-ketamine accelerated postoperative GI recovery and reduced 24 h postoperative pain in patients undergoing open gynecological surgery. TRIAL REGISTRATION: ChiCTR2200055180. Registered on 02/01/2022. It is a secondary analysis of the same trial.

Heme oxygenase-1 inhibits the cytotoxicity of natural killer cells to acute myeloid leukemia by downregulating human leukocyte antigen-C.

BACKGROUND AIMS: Recently, immune escape has been considered as a factor leading to relapse of acute myeloid leukemia (AML). In our previous study, heme oxygenase 1 (HO-1) proved to play an essential role in the proliferation and drug resistance of AML cells. In addition, recent studies by our group have shown that HO-1 is involved in immune escape in AML. Nevertheless, the specific mechanism by which HO-1 mediates immune escape in AML remains unclear. METHODS: In this study, we found that patients with AML and an overexpression of HO-1 had a high rate of recurrence. In vitro, overexpression of HO-1 attenuated the toxicity of natural killer (NK) cells to AML cells. Further study indicated that HO-1 overexpression inhibited human leukocyte antigen-C and reduced the cytotoxicity of NK cells to AML cells, leading to AML relapse. Mechanistically, HO-1 inhibited human leukocyte antigen-C expression by activating the JNK/C-Jun signaling pathway. RESULTS: In AML, HO-1 inhibits cytotoxicity of NK cells by inhibiting the expression of HLA-C, thus causing immune escape of AML cells. CONCLUSIONS: NK cell-mediated innate immunity is important for the fight against tumors, especially when acquired immunity is depleted and dysfunctional, and the HO-1/HLA-C axis can induce functional changes in NK cells in AML. Anti-HO-1 treatment can promote the antitumor effect of NK cells and may play an important role in the treatment of AML.

The phosphorylation of PHF5A by TrkA-ERK1/2-ABL1 cascade regulates centrosome separation.

During interphase, the newly duplicated pairs of centrosomes are held together by a centrosome linker, and the centrosome separation needs the disruption of this linker to induce the duplicated centrosomes separating into two distinct microtubule organization centers. The mechanism of regulating centrosome separation is however poorly understood. Here, we demonstrated that the phosphorylation of PHF5A at Y36 by the TrkA-ERK1/2-ABL1 cascade plays a critical role in regulating centrosome separation. PHF5A, a well-characterized spliceosome component, is enriched in the centrosome. The pY36-PHF5A promotes the interaction between CEP250 and Nek2A in a spliceosomal-independent manner, which leads to premature centrosome separation. Furthermore, the unmatured centrosome remodels the microtubule and subsequently regulates cell proliferation and migration. Importantly, we found that the phosphorylation cascade of TrkA-ERK1/2-ABL1-PHF5A is hyper-regulated in medulloblastoma. The inhibition of this cascade can induce senescence and restrict the proliferation of medulloblastoma. Our findings on this phosphorylation cascade in regulating centrosome separation could provide a series of potential targets for restricting the progress of medulloblastoma.

[Study on the Relationship between Integrin 2A and Drug Resistance in Chronic Myeloid Leukemia].

OBJECTIVE: To explore the expression pattern and clinical significance of Integral membrane protein 2A（ITM2A） in drug resistant patients with chronic myeloid leukemia (CML). METHODS: The expression of ITM2A in CML was evaluated by qRT-PCR, Western blot and immunocytochemistry. In order to understand the possible biological effects of ITM2A, apoptosis, cell cycle and myeloid differentiation antigen expression of CML cells were detected by flow cytometry after over-expression of ITM2A. The nuderlying molecular mechanism of its biological effect was explored. RESULTS: The expression of ITM2A in bone marrow of CML resistant patients was significantly lower than that of sensitive patients and healthy donors（P<0.05）. The CML resistant strain cell K562R was successfully constructed in vitro. The expression of ITM2A in the resistant strain was significantly lower than that in the sensitive strain(P<0.05). Overexpression of ITM2A in K562R cells increased the sensitivity of K562R cells to imatinib and blocked the cell cycle in G2 phase(P<0.05), but did not affect myeloid differentiation. Mechanistically, up-regulation of ITM2A reduced phosphorylation in ERK signaling (P<0.05). CONCLUSION: The expression of ITM2A was low in patients with drug resistance of CML, and the low expression of ITM2A may be the key factor of imatinib resistance in CML.

Heme oxygenase 1 overexpression induces immune evasion of acute myeloid leukemia against natural killer cells by inhibiting CD48.

BACKGROUND: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Given the high relapse rate, more effective treatments are needed to improve clinical outcomes. We previously demonstrated that heme oxygenase 1 (HO1) is overexpressed in AML, while the functional roles of HO1 remain unclear. METHODS: Bioinformatics analysis and flow cytometry were conducted to assess the association between HO1 levels and immune cells or immune checkpoint/ligand molecules in AML patients. Primary natural killer (NK) cells were purified and subsequently co-cultured in vitro with transduced AML cells to determine the effects of HO1 expression on NK cell functions. AML mice models were established to investigate the effects of HO1 expression on cytotoxic effects of NK cells in vivo. The molecular mechanism was studied by flow cytometry, quantitative real-time PCR (qRT-PCR), western blotting, and immunoprecipitation. RESULTS: Bioinformatics analysis indicated a correlation between HO1 expression and the AML immune microenvironment. The present study findings indicated that HO1 specifically downregulates the expression of CD48, a ligand of the NK cell-activating receptor 2B4, thus decreasing the cytotoxic effect of NK cells. HO1 overexpression promoted tumor growth and inhibited the cytotoxic effect of NK cells in the AML mice model. Mechanistic investigations found that HO1 directly interacted with Sirt1 and increased its expression and deacetylase activity. With the overexpression of HO1, increased Sirt1 in AML cells enabled histone H3K27 deacetylation to suppress CD48 transcription and expression. Administration of Sirt1 inhibitor restored the expression of CD48. CONCLUSIONS: Collectively, HO1 promotes NK cell dysfunction in AML. Therefore, restoring NK cell function by inhibiting HO1 activity is a potential immunotherapeutic approach against AML.

Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4.

Drug resistance is a key factor in the treatment failure of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) plays a crucial role in tumor chemotherapy resistance. However, the potential mechanism of Nrf2 regulating DNA mismatch repair (MMR) pathway to mediate gene-instability drug resistance in AML is still unclear. Here, it was found that Nrf2 expression was closely related to the disease progression of AML as well as highly expressed in AML patients with poor prognostic gene mutations. Meanwhile, it was also found that the expression of Nrf2 was significantly negatively correlated with DNA MMR gene replication factor C4 (RFC4) in AML. CHIP analysis combined with luciferase reporter gene results further showed that Nrf2 may inhibit the expression of RFC4 by its interaction with the RFC4 promoter. In vitro and vivo experiments showed that the overexpression of Nrf2 decreased the killing effect of chemotherapy drug cytarabine (Ara-C) on leukemia cells and inhibited the expression of RFC4. Mechanistically, The result that Nrf2-RFC4 axis mediated AML genetic instability drug resistance might be received by activating the JNK/NF-κB signaling pathway. Taken together, these findings may provide a new idea for improving AML drug resistance.

Nrf2 Overexpression Decreases Vincristine Chemotherapy Sensitivity Through the PI3K-AKT Pathway in Adult B-Cell Acute Lymphoblastic Leukemia.

Uncontrolled proliferation is an important cancer cell biomarker, which plays a critical role in carcinogenesis, progression and development of resistance to chemotherapy. An improved understanding of novel genes modulating cancer cell proliferation and mechanism will help develop new therapeutic strategies. The nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, decreases apoptosis when its expression is upregulated. However, the relationship between Nrf2 and Vincristine (VCR) chemotherapy resistance in B-cell acute lymphoblastic leukemia (B-ALL) is not yet established. Our results showed that Nrf2 levels could sufficiently modulate the sensitivity of B-ALL cells to VCRby regulating an apoptotic protein, i.e., the Bcl-2 agonist of cell death (BAD). Chemotherapeutic agents used for the treatment of B-ALL induced Nrf2 overactivation and PI3K-AKT pathway activation in the cells, independent of the resistance to chemotherapy; thus, a potential resistance loop during treatment for B-ALL with a drug combination is established. Therefore, B-ALL patients with a high expression of Nrf2 might mean induction chemotherapy with VCR effective little.

Acetylation dependent translocation of EWSR1 regulates CHK2 alternative splicing in response to DNA damage.

Ewing sarcoma breakpoint region 1 (EWSR1) is a member of FET (FUS/EWSR1/TAF15) RNA-binding family of proteins. The Ewing sarcoma oncoprotein EWS-FLI1 has been extensively studied, while much less is known about EWSR1 itself, especially the potential role of EWSR1 in response to DNA damage. Here, we found that UV irradiation induces acetylation of EWSR1, which is required for its nucleoli translocation. We identified K423, K432, K438, K640, and K643 as the major acetylation sites, p300/CBP and HDAC3/HDAC10 as the major acetyltransferases and deacetylases, respectively. Mechanically, UV-induced EWSR1 acetylation repressed its interaction with spliceosomal component U1C, which caused abnormal splicing of CHK2, suppressing the activity of CHK2 in response to UV irradiation. Taken together, our findings uncover acetylation as a novel regulatory modification of EWSR1, and is essential for its function in DNA damage response.

Plasma cytokines interleukin-18 and C-X-C motif chemokine ligand 10 are indicative of the anti-programmed cell death protein-1 treatment response in lung cancer patients.

BACKGROUND: Although programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint inhibitors have shown prominent efficacy for treatment of advanced lung cancer, the outcomes of metastatic lung cancer remain poor throughout the world. Although progression-free survival (PFS) and overall survival (OS) have improved in the first- and second-line therapy settings for advanced lung cancer, the response rates to PD-1/PD-L1 inhibition range from 20% to 40%. Furthermore, patients may be at risk for immune-related adverse events (irAEs); hence, appropriate patient selection is crucial. This study aimed to identify a panel of plasma cytokines representing prognostic and predictive biomarkers of the response to anti-PD-1/PD-L1 treatment. METHODS: We prospectively studied 32 lung cancer patients who received anti-PD-1/PD-L1 antibody immunotherapy. Plasma cytokines in peripheral blood samples were evaluated and analyzed using flow cytometry at the time of diagnosis and at 2 months after the initiation of PD-1/PD-L1 inhibition. RESULTS: The baseline plasma concentrations of interleukin-18 (IL-18) and C-X-C motif chemokine ligand 10 (CXCL10) were correlated with the degree of tumor response. Moreover, the magnitude of plasma IL-18 and CXCL10 level fluctuations were correlated significantly with the objective tumor response to anti-PD-1/PD-L1 immunotherapy, and patients with high CXCL10 expression had significantly shorter PFS than those with low CXCL10 expression. A strong positive correlation between the fluctuation of IL-18 and interleukin-8 (IL-8) levels was detected, as was a negative correlation between the fluctuation of IL-18 and CXCL10 levels. The level of plasma C-C motif chemokine ligand 5 (CCL5) was significantly higher in patients with irAEs than in those without irAEs. CONCLUSIONS: Plasma cytokines are related to the clinical efficacy of PD-1/PD-L1 inhibitors. IL-18 and CXCL10 are potential predictive markers for anti-PD-1/PD-L1 therapy in lung cancer patients and may play an important role in selecting patients who would benefit from PD-1/PD-L1 inhibitors.