Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAKα-JNK pathway.

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.

Novel CAR T-cell therapies for relapsed/refractory B-cell malignancies: latest updates from 2023 ASH annual meeting.

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.

[Immune Reconstitution after BTKi Treatment in Chronic Lymphocytic Leukemia].

OBJECTIVE: To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia (CLL). METHODS: The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively. RESULTS: The median age of 59 CLL patients was 60.5(36-78). After one year of BTKi treatment, the CLL clones (CD5 +/CD19 +) of 51 cases (86.4%) were significantly reduced, in which the number of cloned-B cells decreased significantly from (46±6.1)×109/L to (2.3±0.4)×109/L (P =0.0013). But there was no significant change in the number of non-cloned B cells (CD19 + minus CD5 +/CD19 +). After BTKi treatment, IgA increased significantly from (0.75±0.09)g/L to (1.31±0.1)g/L (P <0.001), while IgG and IgM decreased from (8.1±0.2)g/L and (0.52±0.6)g/L to (7.1±0.1)g/L and (0.47±0.1)g/L, respectively (P <0.001, P =0.002). BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients, which manifested as both a decrease in total number of T cells from (2.1±0.1)×109/L to (1.6±0.4)×109/L and NK/T cells from (0.11±0.1)×109/L to (0.07±0.01)×109/L (P =0.042, P =0.038), both an increase in number of CD4 + cells from (0.15±6.1)×109/L to (0.19±0.4)×109/L and CD8 + cells from (0.27±0.01)×109/L to (0.41±0.08)×109/L (both P <0.001). BTKi treatment also up-regulated the expression of interleukin (IL)-2 while down-regulated IL-4 and interferon (IFN)-γ. However, the expression of IL-6, IL-10, and tumor necrosis factor (TNF)-α did not change significantly. BTKi treatment could also restored the diversity of TCR and BCR in CLL patients, especially obviously in those patients with complete remission (CR) than those with partial remission (PR). Before and after BTKi treatment, Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001 (P <0.001), while in patients with PR was 0.01±0.03 and 0.05±0.02 (P >0.05), respectively. Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15 (P <0.001), while in patients with PR was 0.15±0.009 and 0.23±0.18 (P <0.05), respectively. CONCLUSIONS: BTKi treatment can shrink the clone size in CLL patients, promote the expression of IgA, increase the number of functional T cells, and regulate the secretion of cytokines such as IL-2, IL-4, and IFN-γ. BTKi also promote the recovery of diversity of TCR and BCR. BTKi treatment contributes to the reconstitution of immune function in CLL patients.

SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: SYT7 regulates the progression of CLL through SYVN1-mediated KNTC1 ubiquitination, which has potential value for molecular targeted therapy of CLL.

The complete chloroplast genome of Indigofera stachyodes (Fabaceae), a traditional Chinese medicinal plant.

Indigofera stachyodes Lindl. is a traditional medicinal plant in southwestern China. In this study, we report the complete chloroplast genome sequence of I. stachyodes, using next-generation sequencing technology. The complete chloroplast genome of I. stachyodes was 158,039 bp in length with an overall GC content 35.80%, containing a large single-copy (LSC) region of 88,772 bp, a small single-copy (SSC) region of 18,733 bp, and a pair of inverted repeats (IRs) regions of 25,267 bp. In total, there are 128 genes (83 protein-coding genes (PCGs), eight ribosomal RNA (rRNA) genes, and 37 tRNA genes) in the whole chloroplast genome, including 113 unique genes (78 unique PCGs, 31 unique tRNAs, and four unique rRNAs). The phylogenetic analysis indicated that I. stachyodes formed a monophyletic clade with I. tinctoria and I. linifolia, showing that they have close relationship. The complete chloroplast genome of I. stachyodes provides valuable genomic information for the phylogeny, molecular identification and sustainable utilization of this species.

The complete chloroplast genome of Periploca forrestii (Apocynaceae), a traditional Chinese medicinal plant.

Periploca forrestii Schltr. is a traditional medicine plant in southwestern China. In this study, we characterize the complete chloroplast (cp) genome of P. forrestii based on next-generation sequencing. The cp genome is 154,140 bp in size with an overall GC content 38.2%, including a large single-copy (LSC) region (84,941 bp), a small single-copy (SSC) region of 17,619 bp, and two inverted repeats (IRs) regions, each of 25,790 bp. A total of 130 genes (85 protein-coding genes, 8 ribosomal RNA (rRNA) genes, and 37 transfer RNA (tRNA genes)) are annotated in the whole chloroplast genome, containing 113 unique genes (79 unique CDSs, 30 unique tRNAs, and 4 unique rRNAs). The phylogenetic analysis indicated that P. forrestii formed a monophyletic clade with the same genus plant P. sepium, showing that they have close relationship. The complete chloroplast genome of P. forrestii provides valuable genomic information for the phylogeny, molecular identification and sustainable utilization of this species.