BACKGROUND: Mitosis-associated genes are dysregulated in many types of cancers and play important roles in disease progression and chemotherapy resistance. However, their expression and functions in chemotherapy-resistant Acute Myeloid Leukemia (AML) are still largely undetermined. OBJECTIVE: This study aims to explore the roles of spindle assembly checkpoint (SAC) genes CENPE, CENPF, and DLGAP5 in chemotherapy-resistant AML. METHODS: RNA-sequencing (RNA-seq) was performed in patients with chemotherapy-resistant AML and chemotherapy-sensitive AML. AML mRNA data from 151 patients with recurrence were downloaded from TCGA. Integrated analysis of the differentially expressed genes (DEGs), GO and KEGG pathways. CENPE, CENPF, or DLGAP5 knockdown cell lines were used to analyse proliferation, apoptosis and cell cycle alterations. RESULTS: A total of 87 DEGs (48 upregulated and 39 downregulated) were obtained through gene analysis of R/R-AML and a total of 329 DEGs (202 upregulated and 127 downregulated) were obtained in refractory S-AML. Upregulated DEGs were mainly enriched in cell cycle (GO: 0007049, hsa04110) and mitotic cell cycle (GO: 0000278) processes and pathway. Venn diagram analysis identified the most upregulated DEGs (including CENPE, CENPF, and DLGAP5) in chemoresistant AML. The expression of CENPE, CENPF and DLGAP5 in R-AML (TCGA) was significantly higher than that of primary AML (GEO). The proliferation of K562 cells after CENPE and DLGAP5 knockdown was significantly decreased (P= 0.0001 and P= 0.0006). In THP-1 cells, the CCK-8 values after CENPE, CENPF and DLGAP5 knockdown were significantly decreased (P= 0.01, P= 0.0395 and P= 0.0362). Knockdown of CENPE, CENPF and DLGAP5 significantly increased cell apoptosis by regulating Caspase-9, BAX, TP-53 and bcl-2, and induced cell cycle arrested by regulating CDK1, CDK2, CDKN1A, and CyclinD1. CONCLUSIONS: In conclusion, the mitotic cell cycle-associated genes CENPE, CENPF, and DLGAP5 were upregulated in chemotherapy-resistant AML patients and might be useful for predicting poor prognosis.

The prognosis of chemoresistant acute myeloid leukemia (AML) is still poor, mainly owing to the sustained proliferation ability of leukemic cells, while the microtubules have a major role in sustaining the continuity of cell cycle. In the present study, we have identified CENPE, a microtubular kinesin-like motor protein that is highly expressed in the peripheral blood of patients with chemoresistant AML. In our in vitro studies, knockdown of CENPE expression resulted in the suppression of proliferation of myeloid leukemia cells and reversal of cytarabine (Ara-C) chemoresistance. Furthermore, Lin28A, one of the RNA-binding oncogene proteins that increase cell proliferation and invasion and contribute to unfavorable treatment responses in certain malignancies, was found to be remarkably correlated with CENPE expression in chemoresistance AML. Overexpression of LIN28A promoted the proliferation and Ara-C chemoresistance of leukemic cells. RIP assay, RNA pull-down, and dual luciferase reporter analyses indicated that LIN28A bound specifically to the promoter region GGAGA of CENPE. In addition, the impacts of LIN28A on cell growth, apoptosis, cell cycle progression, and Ara-C chemoresistance were reverted by the knockdown of CENPE. Hence, Lin28A/CENPE has enhanced the proliferation and chemoresistance of AML, and therefore, it could be a prospective candidate for AML treatment.

Purpose: Red blood cell distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and platelet count (PLT) have been reported to be associated with the prognosis of malignancies; this study aimed to evaluate the prognostic significance of the inflammatory prognostic scoring index (IPSI), comprised of RDW, N LR, and PLT for overall survival (OS) in newly diagnosed multiple myeloma patients in the bortezomib-based chemotherapy era. Patients and methods: The prognostic significance of variables associated with the OS of 175 newly diagnosed multiple myeloma patients was evaluated through univariate and multivariate analyses. The cut-off values of RDW, NLR, and PLT were obtained from references. Patients with high RDW (RDW>14) were given a score of 1; patients with high NLR (NLR>2) or low PLT (PLT≤150) were given a score of 2. According to the obtained scores, the inflammatory prognostic scoring index (IPSI) was formed, in which patients were grouped into high-risk group (4–5 points), intermediate-risk group (3 points) and low-risk group (0–2 points). Results: OS varied significantly in different IPSI groups (P< 0.001). On multivariate analysis, the IPSI was an independent prognostic factor for OS (intermediate-risk group HR 2.89, 95% CI 1.60–5.22, high risk-group HR 14.50, 95% CI 7.26–28.93, P<0.001). Importantly, with IPSI as supplement to the International Staging System (ISS), a significant difference in OS was observed among IPSI subgroups (ISS I, P<0.001; ISS II, P=0.008; ISS III, P<0.001). Conclusion: The IPSI, comprised of RDW, NLR, and PLT, played specific role in the prognosis of patients preliminarily diagnosed with multiple myeloma in the bortezomib-based chemotherapy era and could be a beneficial supplement for ISS staging.

Purpose: To validate the clinical efficacy of the recently developed EUTOS long-term survival (ELTS) score in a real-world setting. Patients and Methods: A total of 479 chronic myeloid leukemia (CML) patients treated with frontline imatinib between January 2010 and December 2017 were enrolled in this retrospective study. The ELTS score was evaluated on the end-points including complete cytogenetic response (CCyR), progression-free survival (PFS), overall survival (OS) and CML-related death, and the efficiency of the ELTS score was further compared with the historical Sokal, Hasford, EUTOS scores. Results: With a median follow-up of 69 months (range, 9– 112 months), 462 evaluable patients were stratified into the ELTS low-risk (n = 230), ELTS intermediate-risk (n = 168) and ELTS high-risk (n = 64) groups. For the regular assessment indicators like CCyR, PFS and OS, the ELTS scoring system could effectively identify the corresponding risk groups, similarly with the results provided by previous scoring systems. With respect to the CML-related death, the ELTS score could accurately identify a high-risk group with a significantly higher risk of dying of CML, and the 5-year cumulative incidence occurred in the ELTS high-, intermediate-, and low-risk groups was 11% (95% CI: 3– 19%), 5% (95% CI: 1– 9%) and 2% (95% CI: 0– 4%), respectively. Most notably, the ELTS score outperformed the Sokal, Hasford and EUTOS scores without statistical difference among different risk groups. Conclusion: The ELTS score could effectively predict the prognosis of imatinib-treated CML patients in real-life settings.

Purpose: The aim of this study was to investigate the antitumor effect of chidamide in combination with bortezomib on gastric cancer cell lines. Materials and Methods: First, the sensitivity and IC₅₀ values of chidamide and bortezomib in several gastric cancer cell lines (MGC-803, BGC-823, SGC-7901, and MKN45) were measured using the CCK-8 assay. Then, the relatively insensitive gastric cancer cell lines (MGC-803 and BGC-823) were treated with low concentrations of chidamide alone, bortezomib alone, or chidamide and bortezomib combination to detect the effects on cell proliferation, apoptosis, migration, and invasion. Finally, the inhibitory effect of the combined chidamide and bortezomib treatment on MGC-803 cells was verified in vivo through tumor formation experiments in nude mice. Results: Compared with low-dose chidamide or bortezomib alone, the low-dose drug combination significantly inhibited the proliferation, migration, and invasion of MGC-803 and BGC-823 cells and induced apoptosis of the cells. The effects of the low-dose chidamide and bortezomib combination reduced the growth on gastric cancer in vivo were investigated by using a subcutaneous tumor mouse model. Conclusion: Our results suggest that the combination of chidamide and bortezomib can significantly reduce the proliferation, invasion, and migration of MGC-803 and BGC-823 cells, providing a framework for the clinical evaluation of combined therapies for gastric cancers.

Background: Hypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined. Purpose: To explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines. Methods: In our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels. Results: Our results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death. Conclusion: Our study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.