Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML.

Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the "don't-eat-me" signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.

Long non-coding RNA MALAT1 sponges miR-149 to promote inflammatory responses of LPS-induced acute lung injury by targeting MyD88.

Acute lung injury (ALI) caused by sepsis occurs early and the condition is severe, and is also an important reason for accelerating the death of patients. Increasing evidence has identified long non-coding RNA (lncRNA) metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) as a regulator of ALI. However, the potential mechanism underlying MALAT1 on ALI still needs further identification. To explore the mechanisms of gene regulation expression mediated by MALAT1 through miR-149/MyD88 in lung injury inflammation, we constructed a lung injury inflammatory model using the lipopolysaccharides (LPS)-induced method and quantificated the cytokines and signaling cascade molecules as well as miR-149. The MALAT1, myeloid differentiation factor 88 (MyD88), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 levels were significantly increased, and the nuclear factor-κB (NF-κB) pathway was activated, but the miR-149 level was decreased in the LPS-induced ALI model. miR-149 directly targeted both lncRNA MALAT1 and the MyD88 gene. Knockdown of MALAT1 down-regulated the levels of MyD88, TNF-α, IL-1ß, and IL-6, and inhibited the NF-κB pathway. However, MALAT1 knockdown up-regulated the expression of miR-149. Overexpression of miR-149 down-regulated MyD88, TNF-α, IL-1ß, and IL-6 levels, and inhibited the NF-κB pathway. MALAT1 acts as a pro-inflammatory factor in ALI via the miR-149/MyD88/NF-κB axis and is therefore a potential novel therapeutic target for ALI treatment.

Genome wide analysis of MADS-box gene family in Brassica oleracea reveals conservation and variation in flower development.

BACKGROUND: MADS-box genes play important roles in vegetative growth and reproductive development and are essential for the correct development of plants (particularly inflorescences, flowers, and fruits). However, this gene family has not been identified nor their functions analyzed in Brassica oleracea. RESULTS: In this study, we performed a whole-genome survey of the complete set of MADS-box genes in B. oleracea. In total, 91 MADS-box transcription factors (TFs) were identified and categorized as type I (Mα, Mß, Mγ) and type II (MIKCC, MIKC*) groups according to the phylogeny and gene structure analysis. Among these genes, 59 were randomly distributed on 9 chromosomes, while the other 23 were assigned to 19 scaffolds and 9 genes from NCBI had no location information. Both RNA-sequencing and quantitative real-time-PCR analysis suggested that MIKC genes had more active and complex expression patterns than M type genes and most type II genes showed high flowering-related expression profiles. Additional quantitative real-time-PCR analysis of pedicel and four flower whorls revealed that the structure of the B.oleracea MIKC genes was conserved, but their homologues showed variable expression patterns compared to those in Arabidopsis thaliana. CONCLUSION: This paper gives a detailed overview of the BolMADS genes and their expression patterns. The results obtained in this study provide useful information for understanding the molecular regulation of flower development and further functional characterization of MADS-box genes in B. oleracea.