MLN4924 is a potent and selective small-molecule inhibitor of NEDD8-activating enzyme, which showed antitumor effect in several types of malignant tumor types. However, the mechanism of action of MLN4924 in acute myeloid leukemia (AML) requires further investigation. Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was conducted to detect the mRNA levels of genes. Gene expression was knocked down by short hairpin RNA (shRNA). Moreover, the protein expression was detected by Western blotting (WB) assay. The proliferation and apoptosis of AML cells were measured by Cell Counting Kit-8 (CCK8) assay and flow cytometry (FCM). In the present study, we observed that the mRNA expression levels of NEDD8, UBA3, UBE2M and RBX1 in AML patients were up-regulated compared with healthy controls, which were correlated with worse overall survival (OS) of patients. Besides, knockdown of UBA3, UBE2M and RBX1 inhibited the NEDDylation of CULs and increased the protein expression of p53 and p21 in MOLM-13 cell line. In AML cells, MLN4924 inhibited cell proliferation, promoted cell apoptosis, and induced cell cycle arrest at the G2/M phase. As revealed by experiments in vivo and in vitro, the NEDDylation of CULs was significantly inhibited and the p53 signaling pathway was activated after MLN4924 treatment. So, we concluded that NEDD8, UBA3, UBE2M and RBX1 may serve as the prognostic biomarkers and novel therapeutic targets for AML. Inhibition of the NEDDylation pathway resulted in an anti-leukemia effect by activating the p53 signaling pathway.

Acute myeloid leukemia (AML) is a rapidly progressing blood cancer. The prognosis of AML can be challenging, emphasizing the need for ongoing research and innovative approaches to improve outcomes in individuals affected by this formidable hematologic malignancy. In this study, we used single-cell RNA sequencing (scRNA-seq) from AML patients to investigate the impact of L-glutamine metabolism-related genes on disease progression. Our analysis revealed increased glutamine-related activity in CD34 + pre-B cells, suggesting a potential regulatory role in tumorigenesis and AML progression. Furthermore, intercellular communication analysis revealed a significant signaling pathway involving macrophage migration inhibitory factor signaling through CD74 + CD44 within CD34 + pre-B cells, which transmit signals to pre-dendritic cells and monocytes. Ligands for this pathway were predominantly expressed in stromal cells, naïve T cells, and CD34 + pre-B cells. CD74, the pertinent receptor, was predominantly detected in a variety of cellular components, including stromal cells, pre-dendritic cells, plasmacytoid dendritic cells, and hematopoietic progenitors. The study’s results provide insights into the possible interplay among these cell types and their collective contribution to the pathogenesis of AML. Moreover, we identified 10 genes associated with AML prognosis, including CCL5, CD52, CFD, FABP5, LGALS1, NUCB2, PSAP, S100A4, SPINK2, and VCAN. Among these, CCL5 and CD52 have been implicated in AML progression and are potential therapeutic targets. This thorough examination of AML biology significantly deepens our grasp of the disease and presents pivotal information that could guide the creation of innovative treatment strategies for AML patients.

The pathological and immune response of individuals with COVID-19 display different dynamics in lung and intestine. Here, we depict the single-cell transcriptional atlas of longitudinally collected lung and intestinal tissue samples from SARS-CoV-2-infected monkeys at 3 to 10 dpi. We find that intestinal enterocytes are degraded at 3 days post-infection but recovered rapidly, revealing that infection has mild effects on the intestine. Crucially, we observe suppression of the inflammatory response and tissue damage related to B-cell and Paneth cell accumulation in the intestines, although T cells are activated in the SARS-CoV-2 infection. Compared with that in the lung, the expression of interferon response-related genes is inhibited, and inflammatory factor secretion is reduced in the intestines. Our findings indicate an imbalance of immune dynamic in intestinal mucosa during SARS-CoV-2 infection, which may underlie ongoing rectal viral shedding and mild tissue damage.