STAT5 phosphorylation plus minimal residual disease defines a novel risk classification in adult B-cell acute lymphoblastic leukaemia.

The dysregulation of the Janus family tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) is closely related to acute lymphoblastic leukaemia (ALL), whereas the clinical value of phosphorylated STAT5 (pSTAT5) remains elusive. Herein we performed a prospective study on clinical significance of flow cytometry-based pSTAT5 in adult B-ALL patients. A total of 184 patients were enrolled in the Precision-Classification-Directed-Target-Total-Therapy (PDT)-ALL-2016 cohort between January 2018 and December 2021, and STAT5 phosphorylation was detected by flow cytometry at diagnosis. Based on flow-pSTAT5, the population was classified into pSTAT5low (113/184, 61.1%) and pSTAT5high (71/184, 38.9%). Overall survival (OS) and event-free survival (EFS) were inferior in pSTAT5high patients than in those with pSTAT5low (OS, 44.8% vs. 65.2%, p = 0.004; EFS, 23.5% vs. 52.1%, p < 0.001), which was further confirmed in an external validation cohort. Furthermore, pSTAT5 plus flow-based minimal residual disease (MRD) postinduction defines a novel risk classification as being high risk (HR, pSTAT5high + MRD+), standard risk (SR, pSTAT5low + MRD-) and others as moderate-risk group. Three identified patient subgroups are distinguishable with disparate survival curves (3-year OS rates, 36.5%, 56.7% and 76.3%, p < 0.001), which was confirmed on multivariate analysis (hazard ratio 3.53, p = 0.003). Collectively, our study proposed a novel, simple and flow-based risk classification by integrating pSTAT5 and MRD in favour of risk-guided treatment for B-ALL.

Prognostic impact of TP53 mutations in adult acute lymphoblastic leukemia treated with a pediatric-type regimen.

The prognostic impact of TP53 mutations (TP53mut) in adult acute lymphoblastic leukemia (ALL) remains debatable. Herein, we determined the clinical significance of TP53mut in 283 adult ALL patients treated with a pediatric-type regimen. TP53mut were found in 11.0% (31) of patients, including 19 cases in adolescent and young adult (AYA) patients and 12 cases in non-AYA patients. Patients with TP53mut had poorer overall survival (OS) and event-free survival (EFS) in the non-AYA subgroup (n = 64) (3-year OS, 18.2% vs 50.9%, p = .0033; 3-year EFS, 0 vs 45.3%, p = .00028). however, this had to be taken cautiously due to a limited number of patients. In the AYA subgroup (n = 219), TP53mut did not impact OS or EFS (3-year OS, 60.6%vs71.0%, p = .55; 3-year EFS, 52.5%vs59.6%, p = .57). Collectively, our data reveal that the pediatric-type regimen eliminated the poor prognostic impact of TP53mut in AYA ALL. However, in non-AYA ALL patients, TP53mut remain a potential biomarker associated with poor outcomes.

Circ_0025039 acts an oncogenic role in the progression of non-small cell lung cancer through miR-636-dependent regulation of CORO1C.

Non-small cell lung cancer remains the leading cause of cancer-related death worldwide. Circular RNA plays vital roles in NSCLC progression. This study is designed to reveal the role of circ_0025039 in NSCLC cell malignancy. The RNA expression of circ_0025039, microRNA-636 (miR-636), and coronin 1C was detected by quantitative real-time polymerase chain reaction. Protein expression was checked by Western blot analysis or immunohistochemistry assay. Cell proliferation, migration, invasion, tube formation ability, sphere formation capacity, and apoptosis were investigated by cell counting kit-8, 5-Ethynyl-29-deoxyuridine, transwell assay, tube formation assay, sphere formation assay, and flow cytometry analysis, respectively. Mouse model assay was conducted to reveal the effect of circ_0025039 silencing on tumor formation in vivo. The interaction between miR-636 and circ_0025039 or CORO1C was identified through dual-luciferase reporter and RNA pull-down assays. The expression of circ_0025039 and CORO1C was significantly increased, while miR-636 was decreased in NSCLC tissues and cells compared with controls. Circ_0025039 depletion repressed NSCLC cell proliferation, migration, invasion, tube-forming capacity, and sphere formation ability, but induced cell apoptosis. The neoplasm formation was repressed after circ_0025039 silencing. Additionally, circ_0025039 acted as a sponge for miR-636, which was found to target CORO1C. Importantly, the contribution of circ_0025039 to NSCLC progression was mediated by miR-636/CORO1C axis. Circ_0025039 silencing repressed NSCLC malignant progression by reducing CORO1C expression through miR-636, showing the possibility of circ_0025039 as a therapeutic target for NSCLC.

Blockade of SDF-1/CXCR4 reduces adhesion-mediated chemoresistance of multiple myeloma cells via interacting with interleukin-6.

Resistance to chemotherapy represents a major cause for treatment failure in multiple myeloma (MM). Herein, this study was conducted to explore the effect of SDF-1/CXCR4 and interleukin-6 (IL-6) in MM cell adhesion-mediated chemoresistance. Enzyme-linked immunosorbent assay was applied to detect expressions of SDF-1α and IL-6 in MM patients and healthy controls. RPMI-8226 cells and isolated bone marrow stromal cells (BMSCs) were stimulated using recombinant SDF-1α and IL-6. Effect of cocultured BMSCs and RPMI-8226 cells on chemosensitivity and apoptosis of RPMI-8226 cells was analyzed. Effect of doxorubicin on the adhesion rate of RPMl-8226 cells to BMSCs was analyzed by calcitonin test. Effect of SDF-1α-induced upregulation of IL-6 on chemotherapeutic resistance and apoptosis of RPMI-8226 cells in adhesion state was analyzed. Cell adhesion model was treated with recombinant protein SDF-1α and phosphoinositide 3-kinase (P13K) inhibitor Wortmarmin. The levels of P13K and protein kinase B (AKT) and its phosphorylation as well as the expression of IL-6 were analyzed. SDF-1α was positively correlated with IL-6. Recombinant human SDF-1α increased IL-6 expression and induced IL-6 secretion in a time- and dose-dependent manner in BMSCs, which was inhibited by IL-6 and SDF-1α neutralizing antibodies. Coculture of MM cells with BMSCs increased the drug resistance and inhibited the apoptosis on MM cells. SDF-1α-induced IL-6 upregulation mediates chemoresistance and apoptosis of RPMI-8226 cells in adhesion state. SDF-1α may up-regulate the expression of IL-6 by activating the P13K/AKT signaling pathway. SDF-1/CXCR4 may up-regulate the expression of IL-6 through the activation of the P13K/AKT signaling pathway, thereby affecting the chemoresistance mediated by adhesion in MM cells.

Alterations of anticoagulant proteins and soluble endothelial protein C receptor in thalassemia patients of Chinese origin.

BACKGROUND: Thalassemia is characterized by a hypercoagulable state in which the protein C (PC) pathway controls thrombosis. We investigated changes in PC, protein S (PS), antithrombin III (AT III) and soluble endothelial protein C receptor (sEPCR) in thalassemia. METHODS: A group of 129 patients with ß-thalassemia major (ß-TM), ß-thalassemia intermedia (ß-TI), α-thalassemia intermedia (α-TI) and combined α-/ß-thalassemia (α + ß-thal) were compared with 32 gender- and age-matched controls. PC, PS, AT III, sEPCR, thrombin-antithrombin complex (TAT), and intercellular adhesion molecule1 (ICAM-1) antigens were measured by enzyme-linked immunosorbent assay. PC, AT III, and PS activity were assayed by substrate chromatography and a prothrombin time (PT)-based free protein S assay. RESULTS: PC deficiency was seen in 95.3% of the patients and PS deficiency was seen in 77.5%. Concomitant reductions in PC and AT III antigen and activity were observed in ß-TM, ß-TI, and α-TI than in controls (p < 0.005). PC activity was lower in ß-TM than in α-TI (p = 0.004). PS antigen was elevated in ß-TM (p = 0.011) and sEPCR was elevated in α-TI (p = 0.018). Nonsplenectomized patients had lower PC (p = 0.001) and PS (p = 0.006) and higher sEPCR (p = 0.021) than postsplenectomy patients. Transfusion dependent thalassemia (TDT) patients had lower PC levels (p < 0.005) than those with nontransfusion dependent thalassemia (NTDT). ICAM-1 was increased in patient subgroups (p < 0.001), especially those with splenectomies (p = 0.009), and TAT was increased in all patient subgroups compared with controls (p < 0.001) except for α + ß-thal. CONCLUSIONS: Deficiencies of anticoagulant proteins and elevated sEPCR contributed to chronic hypercoagulability in these thalassemia patients of Chinese origin. Splenectomy alleviated these alterations in this patient cohort with the median duration since splenectomy of two years. Blood transfusion was not ideal for avoiding thrombosis.