Histone deacetylase 1 induced by neddylation inhibition contributes to drug resistance in acute myelogenous leukemia.

OBJECTIVE: This study aimed to investigate the function and mechanism of neddylation of HDAC1 underlying drug resistance of AML cells. METHODS: Evaluation experiments of effects of HDAC1 on drug resistance of AML cells were performed with AML cell transfected with constructs overexpressing HDAC1 or multi-drug resistance AML cells transfected with siRNA for HDAC1 through observing cell viability, percentage of apoptotic cell, doxorubicin-releasing index and multidrug resistance associated protein 1 (MRP1) expression. Neddylation or ubiquitination of HDAC1 was determined by immunoprecipitation or Ni2+ pull down assay followed by western blot. The role of HDAC1 was in vivo confirmed by xenograft in mice. RESULTS: HDAC1 was significantly upregulated in refractory AML patients, and in drug-resistant AML cells (HL-60/ADM and K562/A02). Intracellular HDAC1 expression promoted doxorubicin resistance of HL-60, K562, and primary bone marrow cells (BMCs) of remission AML patients as shown by increasing cell viability and doxorubicin-releasing index, inhibiting cell apoptosis. Moreover, HDAC1 protein level in AML cells was regulated by the Nedd8-mediated neddylation and ubiquitination, which further promoted HDAC1 degradation. In vivo, HDAC1 overexpression significantly increased doxorubicin resistance; while HDACs inhibitor Panobinostat markedly improved the inhibitory effect of doxorubicin on tumor growth. Furthermore, HDAC1 silencing by Panobinostat and/or lentivirus mediated RNA interference against HDAC1 effectively reduced doxorubicin resistance, resulting in the inhibition of tumor growth in AML bearing mice. CONCLUSION: Our findings suggested that HDAC1 contributed to the multidrug resistance of AML and its function turnover was regulated, at least in part, by post-translational modifications, including neddylation and ubiquitination.

Gut-lung axis and asthma: A historical review on mechanism and future perspective.

BACKGROUND: Gut microbiota are closely related to the development and regulation of the host immune system by regulating the maturation of immune cells and the resistance to pathogens, which affects the host immunity. Early use of antibiotics disrupts the homeostasis of gut microbiota and increases the risk of asthma. Gut microbiota actively interact with the host immune system via the gut-lung axis, a bidirectional communication pathway between the gut and lung. The manipulation of gut microbiota through probiotics, helminth therapy, and fecal microbiota transplantation (FMT) to combat asthma has become a hot research topic. BODY: This review mainly describes the current immune pathogenesis of asthma, gut microbiota and the role of the gut-lung axis in asthma. Moreover, the potential of manipulating the gut microbiota and its metabolites as a treatment strategy for asthma has been discussed. CONCLUSION: The gut-lung axis has a bidirectional effect on asthma. Gut microecology imbalance contributes to asthma through bacterial structural components and metabolites. Asthma, in turn, can also cause intestinal damage through inflammation throughout the body. The manipulation of gut microbiota through probiotics, helminth therapy, and FMT can inform the treatment strategies for asthma by regulating the maturation of immune cells and the resistance to pathogens.

Novel oncoprotein EPS8: a new target for anticancer therapy.

EPS8 was first identified as a tyrosine kinase substrate, that plays a role in EGFR-mediated mitogenic signaling. Recent research has shown that EPS8 is overexpressed in most types of cancer, for example breast cancer, colon cancer, cervical cancer and even hematologic malignancies. EPS8 is involved in many signaling pathways related to tumorigenesis, proliferation, migration and metastasis, and is a biomarker for poor prognosis of cancer patients. This review aims to provide a comprehensive picture of the role of EPS8 in cellular processes and its significance to tumorigenesis. Furthermore, this review focuses on the potential role of EPS8 as a therapeutic cancer target.

KIR2DL1-HLA signaling pathway: notable inhibition in the cytotoxicity of allo-NK cell against KG1A cell.

BACKGROUND: KIR2DL1 is an important member of killer cell immunoglobulin-like receptors (KIRs). It recognizes the C2 group of alleles exclusively and delivers signals that inhibit NK cell cytotoxicity. METHODS: In this study, NK cells were isolated by magnetic activated cell sorting (MACS) from peripheral blood of 12 healthy unrelated male donors. Flow cytometry (FCM) was used to evaluate the purity of NK cells and phenotypic KIR2DL1 expression on them. The lysis of KG1A and K562 cells by NK cells was analyzed in the lactate dehydrogenase (LDH) assay to investigate whether KIR2DL1 expression on NK cells would affect the cytotoxicity. RESULTS: Significant differences in KIR2DL1 frequency were noted among the donors (range, 27.14% - 92.49%). NK cells with lower KIR2DL1 expression exerted higher cytolytic activity against KG1A cells, whereas those with higher KIR2DL1 expression exerted significantly lower lysis against KG1A cells (R2 = 0.8169, p < 0.05). CONCLUSIONS: KIR2DL1 expression frequency was negatively correlated with the cytotoxicity of NK cells against KG1A cells. This study discovered that differential KIR2DL1 expression could positively affect the lytic activity of NK cells against KG1A cells, suggesting potential clinical value of KIR2DL1 selection in the treatment of acute myeloid leukemia (AML) patients.

An Autophagy-Related Gene Signature can Better Predict Prognosis and Resistance in Diffuse Large B-Cell Lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease, and about 30%-40% of patients will develop relapsed/refractory DLBCL. In this study, we aimed to develop a gene signature to predict survival outcomes of DLBCL patients based on the autophagy-related genes (ARGs). Methods: We sequentially used the univariate, least absolute shrinkage and selector operation (LASSO), and multivariate Cox regression analyses to build a gene signature. The Kaplan-Meier curve and the area under the receiver operating characteristic curve (AUC) were performed to estimate the prognostic capability of the gene signature. GSEA analysis, ESTIMATE and ssGSEA algorithms, and one-class logistic regression were performed to analyze differences in pathways, immune response, and tumor stemness between the high- and low-risk groups. Results: Both in the training cohort and validation cohorts, high-risk patients had inferior overall survival compared with low-risk patients. The nomogram consisted of the autophagy-related gene signature, and clinical factors had better discrimination of survival outcomes, and it also had a favorable consistency between the predicted and actual survival. GSEA analysis found that patients in the high-risk group were associated with the activation of doxorubicin resistance, NF-κB, cell cycle, and DNA replication pathways. The results of ESTIMATE, ssGSEA, and mRNAsi showed that the high-risk group exhibited lower immune cell infiltration and immune activation responses and had higher similarity to cancer stem cells. Conclusion: We proposed a novel and reliable autophagy-related gene signature that was capable of predicting the survival and resistance of patients with DLBCL and could guide individualized treatment in future.

[Efficacy and Safety of Cladribine-based Intensified Conditioning Regimen in Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia].

OBJECTIVE: To investigate the efficacy, safety and the risk factors affecting prognosis of high-risk acute myeloid leukemia (AML) patients treated by cladribine-based intensified conditioning regimen. METHODS: The clinical data of 28 patients with high-risk AML treated by cladribine in combination with busulfan plus cyclophosphamide (BuCy) intensified conditioning regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Zhujiang Hospital, Southern Medical University from October 2016 to June 2020 were analyzed retrospectively. The overall survival (OS) rate, cumulative progression-free survival (PFS) rate, relapse rate, non-relapse mortality (NRM), regimen related toxicity (RRT) and risk factors affecting prognosis of the patients were analyzed. RESULTS: The 1-year OS and PFS of the patients after implantation was (78.8±8.6)% and (79.8±8.1)%, while the 1-year cumulative relapse rate and NRM of the patients was 9.3% and 22.0%, respectively. The 1-year expected OS of MRD- high-risk patients before HSCT was 100%. The 1-year expected OS and PFS of the patients in pre-transplant relapse group was (46.9±18.7)% and (50.0±17.7)%, respectively. The incidence of I/II grade RRT was 39.3%. NO III/IV grade RRT were found in 28 patients. Multivariate analysis showed that pre-transplant relapse was the independent risk factor affecting OS and PFS of the patients. CONCLUSION: The intensified conditioning regimen of cladribine in combination with BuCy can reduce the relapse rate of high-risk AML transplantation, and its RRT is mild, exhibiting good safety. MRD- high-risk patients before HSCT can achieve better transplant benefits, but the prognosis of patients with relapse before transplantation is not significantly improved. Therefore, for non-relapsed high-risk AML patients, this intensified conditioning regimen deserves to be considered.

Current perspectives on the treatment of double hit lymphoma.

Introduction: Double hit lymphoma (DHL) represents a new diagnostic category with genetic, immunohistochemical and clinical characteristics intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Patients with DHL usually experience poor survival after frontline R-CHOP treatment and require alternative therapies. However, the ideal therapeutic options remain undefined. Areas covered: Traditional therapies for the treatment of DHL are discussed, including intensive induction, hematopoietic stem cell transplantation (HSCT), methotrexate CNS-directed prophylaxis, and radiation therapy. The authors further introduce small-molecule inhibitors targeting myc or bcl-2 signaling pathways, chimeric antigen receptor T-cell therapy, programmed death-1 monoclonal antibody and immunomodulatory drugs as novel approaches. Expert opinion: No standard treatment exists for DHL. At present, DA-EPOCH-R exhibits an upfront induction option. Central nervous system prophylaxis with methotrexate is recommended as part of the induction therapy. For those who do not obtain complete remission, HSCT or clinical trials should be considered. Targeted approaches, especially chimeric antigen receptor T-cell therapies and small-molecule inhibitors targeting myc or bcl-2, exhibit the potential of improving outcomes for patients with DHL. High-throughput sequencing is a promising technique both at diagnosis and relapse, in order to predict outcomes and potential novel therapies.

IL-2Rα up-regulation is mediated by latent membrane protein 1 and promotes lymphomagenesis and chemotherapy resistance in natural killer/T-cell lymphoma.

BACKGROUND: Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma often resistant to chemotherapy. Serum level of soluble IL-2 receptor α (IL-2Rα) is elevated in NKTCL patients and correlates significantly with treatment response and survival. In the current study we examined the potential role of IL-2Rα by over-expressing IL-2Rα in representative cell lines. METHODS: Levels of IL-2Rα were evaluated in the human natural killer cell line NK-92 and the NKTCL cell line SNK-6. Lentiviral vectors were used to express latent membrane protein 1 (LMP1) in NK-92 cells, and IL-2Rα in both NK-92 and SNK-6 cells. The biological effects of these genes on proliferation, apoptosis, cell cycle distribution, and chemosensitivity were analyzed. RESULTS: Expression of IL-2Rα was significantly higher in SNK-6 cells than in NK-92 cells. Expressing LMP1 in NK-92 cells remarkably up-regulated IL-2Rα levels, whereas selective inhibitorss of the proteins in the MAPK/NF-κB pathway significantly down-regulated IL-2Rα. IL-2Rα overexpression in SNK-6 cells promoted cell proliferation by altering cell cycle distribution, and induced resistance to gemcitabine, doxorubicin, and asparaginase. These effects were reversed by an anti-IL-2Rα antibody. CONCLUSIONS: Our results suggest that LMP1 activates the MAPK/NF-κB pathway in NKTCL cells, up-regulating IL-2Rα expression. IL-2Rα overexpression promotes growth and chemoresistance in NKTCL, making this interleukin receptor a potential therapeutic target.

[Correlation of IKZF1 Gene with Malignant Tumors and Systemic Lupus Erythematosus].

IKZF1 gene located in 7p12 of chromosome, and Ikaros family zinc finger encoded by IKZF1, are lymphoid-restricted transcription factors. In recent years, it has been demonstrated that the mutation of IKZF1 gene involved in proliferation, metastasis and prognosis of many malignant tumor except acute lymphoblastic leukemia, and also involved in complex phenotypes and susceptibility to systemic lupus erythematosus. This review briefly introduces the molecular structure and physiological function of Ikaros, focusing on its function and molecular mechanism in proliferation, metastasis and prognosis of malignant tumors, and its role in the systemic lupus erythematosus.

Overexpression of EPS8 is associated with poor prognosis in patients with acute lymphoblastic leukemia.

Molecular markers have become an invaluable tool in monitoring disease status particularly of leukemias, as bone marrow samples can be easily collected for analysis during all stages of disease development including diagnosis, treatment, and follow-up. Two genes that have been used as prognostic markers in acute leukemia are Wilms' tumor (WT1) and multidrug resistance-1 (MDR1). A novel gene, epidermal growth factor receptor pathway substrate 8 (EPS8), is often over-expressed and associated with poor outcome in some solid tumor types. However, whether EPS8 is also associated with the development of acute lymphoblastic leukemia (ALL) is unclear. Here, quantitative real-time PCR was used to evaluate the expression of EPS8, MDR1, and WT1 in bone marrow samples of adult ALL patients (n=107) and non-leukemia controls (n=22). EPS8, MDR1, and WT1 were detected in ALL patients, and significant correlations were found between expression profiles for EPS8 and MDR1, EPS8 and WT1, and MDR1 and WT1. In general, high expression of EPS8, MDR1, or WT1 in patients was associated with a higher risk of relapse. Furthermore, when patients were stratified based on high or low expression of the genes, Kaplan-Meier survival analysis indicated that disease-free survival of patients with the high-EPS8/high-WT1/high-MDR1 profile was significantly shorter than in patients with the low-EPS8/low-WT1/low-MDR1 profile or those excluded from either of these groups (P<0.0001). Thus, EPS8, as MDR1 and WT1, may be a clinically valuable biomarker for assessing the outcome of ALL patients.

[Recent research progress on the relation of B-ALL associated cytogenetic and molecular genetic abnormalities with B-ALL prognosis].

In recent years, standardized treatment based on the risk stratification has been applied to clinical diagnosis and treatment of leukemia, which significantly improves the remission rate of ALL. However, relapse after remission remains an important challenge for long term efficacy. Chromosomal karyotype analysis is often used clinically to study the genetic features of ALL. As leukemia-specific markers, the cytogenetic and molecular genetic abnormalities can be used to evaluate prognosis and make an effective and optimal therapy. Furthermore, they are also used to track minimal residual disease. Therefore, the cytogenetic and molecular genetic abnormalities may become a monitor and a new target for the treatment of leukemia. This review briefly introduces the structure and physiological function of B-ALL associated cytogenetic and molecular genetic abnormalities, focusing on their prognostic effect on B-ALL.

[Correlation of Eps8 with proliferation, metastasis and prognosis of malignant tumors].

Epidermal growth factor receptor pathway substrate 8 (Eps8) is one of crucial kinase substrates for the epidermal growth factor receptors. Eps8 is related to mitosis and differentiation of normal cells. In recent years, it has been demonstrated that Eps8 involves in proliferation, metastasis and prognosis of many malignant tumors. Experiments have shown that Eps8 involves in Ras-Rac pathway of EGFR signaling by forming Eps8-Abi1-Sos1 tri-complex or participates in endocytosis mediated by rab5. Furthermore, Eps8 has also been found to regulate cell cycle. In conclusion, it may become a monitor and a new target for the treatment of malignant tumors. This review briefly introduces molecular structure and physiological function of Eps8, focusing on its function and molecular mechanism in proliferation, metastasis and prognosis of malignant tumors.