Arsenic trioxide (ATO) has exhibited remarkable efficacy in treating acute promyelocytic leukemia (APL), primarily through promoting the degradation of the PML-RARα fusion protein. However, ATO alone fails to confer any survival benefit to non-APL acute myeloid leukemia (AML) patients and exhibits limited efficacy when used in combination with other agents. Here, we explored the general toxicity mechanisms of ATO in APL and potential drugs that could be combined with ATO to exhibit synergistic lethal effects on other AML. We demonstrated that PML-RARα degradation and ROS upregulation were insufficient to cause APL cell death. Based on the protein synthesis of different AML cells and their sensitivity to ATO, we established a correlation between ATO-induced cell death and protein synthesis. Our findings indicated that ATO induced cell death by damaging nascent polypeptides and causing ribosome stalling, accompanied by the activation of the ZAKα-JNK pathway. Furthermore, ATO-induced stress activated the GCN2–ATF4 pathway, and ribosome-associated quality control cleared damaged proteins with the assistance of p97. Importantly, our data revealed that inhibiting p97 enhanced the effectiveness of ATO in killing AML cells. These explorations paved the way for identifying optimal synthetic lethal drugs to enhance ATO treatment on non-APL AML.
Immunogenic cell death (ICD) is capable of activating the anti-tumor immune response of the organism; however, it is concurrently a complex process involving multiple factors. The specific factors that impact the occurrence of ICD remain undefined.
Abstract Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials.
Chronic lymphocytic leukemia (CLL) is one of the most frequent occurring types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. At present, the molecular mechanism driving the pathogenesis and progression of CLL is not fully understood. The protein Synaptotagmin 7 (SYT7) encoded by the SYT7 gene has been found to be closely related to the development of various solid tumors, but its role in CLL is unclear. In this study, we investigated the function and molecular mechanism of SYT7 in CLL.The expression level of SYT7 in CLL was determined by immunohistochemical staining and qPCR. The role of SYT7 in promoting CLL development was verified by in vivo and in vitro experiments. The molecular mechanism of SYT7 in CLL was elucidated by methods such as GeneChip analysis and Co-immunoprecipitation assay.Malignant behaviors such as proliferation, migration, and anti-apoptosis of CLL cells were significantly inhibited after SYT7 gene knockdown. In contrast, SYT7 overexpression promoted CLL development in vitro. Consistently, the knockdown of SYT7 also inhibited xenograft tumor growth of CLL cells. Mechanistically, SYT7 promoted CLL development by inhibiting SYVN1-mediated KNTC1 ubiquitination. The KNTC1 knockdown also attenuated the effects of SYT7 overexpression on development of CLL.SYT7 regulates the progression of CLL through SYVN1-mediated KNTC1 ubiquitination, which has potential value for molecular targeted therapy of CLL.
This retrospective study aimed to stress the advantages of autologous hematopoietic stem cell transplantation (auto-HSCT) in treating primary MM. Ninety-four MM patients who underwent initial parallel sequential auto-HSCT were selected. Data on efficacy (efficacy evaluation, renal function and hemoglobin recovery), immune reconstitution (B-cell subsets, immunoglobulin levels, T-cell subsets, NK cells, neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR)) and hematopoietic reconstitution times were collected and analyzed. Whether in all selected patients or in groups R-ISS II-III, there was a notable increase in the proportion of patients achieving in a very good partial response (VGPR) or better (P < 0.001, P = 0.02) and a complete response (CR) or better (P = 0.007, P = 0.014) after transplantation compared to the pre-transplant status. Post-Transplant Immune Reconstitution Analysis (Baseline vs. Pre-Transplant and Pre-Transplant vs. Post-Transplant): The level of CD19 + B cells, CD20 + B cells, CD22 + B cells, CD3 + T cells, IgG and LMR showed the same change trend, that is, it decreased before transplantation (P < 0.001, P < 0.001, P < 0.001, P < 0.001, P<0.007, P < 0.001) and then increased significantly after transplantation(P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001, P < 0.001). CD3 + CD4 + T cells from 545.97 (342.11,708.60)/µL to 342.93 (168.38, 475.52)/µL (P < 0.001) and then to 251.48 (188.52, 406.98)/µL (P = 0.348); CD3 + CD8 + T cells from 391.36 (242.19, 563.37)/µL to 337.23 (192.54, 505.96)/µL (P = 0.065) and then to 797.96 (514.49, 1198.03)/µL (P < 0.001), so the CD3 + CD4+/CD3 + CD8 + T cell ratio still remained inverted post-transplant. NK cells changed from 309.86 (206.33, 460.96)/µL to 258.31 (160.75, 436.68)/ µL (P = 0.229) and then to 151.08 (108.17, 240.84)/µL (P = 0.007). Auto-HSCT can promote prolonged remission in patients with MM and also overcome some high-risk factors to achieve superior efficacy in group R-ISS II-III. Patients were immunodeficient before transplantation and auto-HSCT facilitated immune reconstitution.
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