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Blood Dec 2023Acute 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...
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.
Topics: Animals; Mice; Histones; Tumor Suppressor Protein p53; Mutation; Methylation; Nucleotidyltransferases; Leukemia, Myeloid, Acute; Immunity; Polyploidy
PubMed: 37738460
DOI: 10.1182/blood.2023019782 -
Science Advances Jul 2023To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells...
To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)-derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.
Topics: Polyploidy; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Humans; Female; Mifepristone; Drug Resistance, Neoplasm; Cellular Senescence; Cell Line, Tumor; Apoptosis
PubMed: 37478190
DOI: 10.1126/sciadv.adf7195 -
Trends in Genetics : TIG Dec 2023The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However,... (Review)
Review
The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However, failures in cell division can induce a whole-genome doubling (WGD) event, in which diploid cells transition to a tetraploid state. While some WGDs are developmentally programmed to produce nonproliferative tetraploid cells with specific cellular functions, unscheduled WGDs can be catastrophic: erroneously arising tetraploid cells are ill-equipped to cope with their doubled cellular and chromosomal content and quickly become genomically unstable and tumorigenic. Deciphering the genetics that underlie the genesis, physiology, and evolution of whole-genome doubled (WGD) cells may therefore reveal therapeutic avenues to selectively eliminate pathological WGD cells.
Topics: Humans; Tetraploidy; Neoplasms; Cell Division; Genome; Cell Physiological Phenomena
PubMed: 37714734
DOI: 10.1016/j.tig.2023.08.004 -
Science (New York, N.Y.) Aug 2023Polyploid cells, which have extra copies of their genomes, may help tissues respond to injuries and species survive cataclysms.
Polyploid cells, which have extra copies of their genomes, may help tissues respond to injuries and species survive cataclysms.
PubMed: 37616350
DOI: 10.1126/science.adk4276 -
The EMBO Journal Oct 2023Unscheduled increases in ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of...
Unscheduled increases in ploidy underlie defects in tissue function, premature aging, and malignancy. A concomitant event to polyploidization is the amplification of centrosomes, the main microtubule organization centers in animal cells. Supernumerary centrosomes are frequent in tumors, correlating with higher aggressiveness and poor prognosis. However, extra centrosomes initially also exert an onco-protective effect by activating p53-induced cell cycle arrest. If additional signaling events initiated by centrosomes help prevent pathology is unknown. Here, we report that extra centrosomes, arising during unscheduled polyploidization or aberrant centriole biogenesis, induce activation of NF-κB signaling and sterile inflammation. This signaling requires the NEMO-PIDDosome, a multi-protein complex composed of PIDD1, RIPK1, and NEMO/IKKγ. Remarkably, the presence of supernumerary centrosomes suffices to induce a paracrine chemokine and cytokine profile, able to polarize macrophages into a pro-inflammatory phenotype. Furthermore, extra centrosomes increase the immunogenicity of cancer cells and render them more susceptible to NK-cell attack. Hence, the PIDDosome acts as a dual effector, able to engage not only the p53 network for cell cycle control but also NF-κB signaling to instruct innate immunity.
Topics: Animals; Centrosome; Inflammation; Monitoring, Immunologic; Neoplasms; NF-kappa B; Tumor Suppressor Protein p53; Humans
PubMed: 37530438
DOI: 10.15252/embj.2023113510 -
Yi Chuan = Hereditas Sep 2023Autotetraploid rice is a type of germplasm developed from the whole genome duplication of diploid rice, leading to large grains, high nutrient content, and resistance.... (Review)
Review
Autotetraploid rice is a type of germplasm developed from the whole genome duplication of diploid rice, leading to large grains, high nutrient content, and resistance. However, its low fertility has reduced yield and hampered commercialization. To address this issue, a new type of high fertility tetraploid rice was developed, which may serve as a useful germplasm for polyploid rice breeding. In this review, we summarize the progress made in understanding the cellular and molecular genetic mechanisms underlying the low fertility of autotetraploid rice and its F hybrid, as well as the main types of new tetraploid rice with high fertility. Lastly, the idea of utilizing the multi-generation heterosis of neo-tetraploid rice in the future is proposed as a reference for polyploid rice breeding.
Topics: Oryza; Tetraploidy; Plant Breeding; Cytoplasm; Polyploidy
PubMed: 37731232
DOI: 10.16288/j.yczz.23-074 -
Kidney International Oct 2023Tubulointerstitial fibrosis is considered the final convergent pathway of progressive chronic kidney diseases (CKD) regardless of etiology. However, mechanisms...
Tubulointerstitial fibrosis is considered the final convergent pathway of progressive chronic kidney diseases (CKD) regardless of etiology. However, mechanisms underlying kidney injury-induced fibrosis largely remain unknown. Recent studies have indicated that transcriptional intermediary factor 1γ (TIF1γ) inhibits the progression of fibrosis in other organs. Here, we found that TIF1γ was highly expressed in the cytoplasm and nucleus of the kidney proximal tubule. Interestingly, we found tubular TIF1γ expression was decreased in patients with CKD, including those with diabetes, hypertension, and IgA nephropathy, and in mouse models with experimental kidney fibrosis (unilateral ureteral obstruction [UUO], folic acid nephropathy [FAN], and aristolochic acid-induced nephrotoxicity). Tubule-specific knock out of TIF1γ in mice exacerbated UUO- and FAN-induced tubular cell polyploidy and subsequent fibrosis, whereas overexpression of kidney TIF1γ protected mice against kidney fibrosis. Mechanistically, in tubular epithelial cells, TIF1γ exerted an antifibrotic role via transforming growth factor-β (TGF-β)-dependent and -independent signaling. TIF1γ hindered TGF-β signaling directly by inhibiting the formation and activity of the transcription factor Smad complex in tubular cells, and we discovered that TIF1γ suppressed epidermal growth factor receptor (EGFR) signaling upstream of TGF-β signaling in tubular cells by ubiquitylating EGFR at its lysine 851/905 sites thereby promoting EGFR internalization and lysosomal degradation. Pharmacological inhibition of EGFR signaling attenuated exacerbated polyploidization and the fibrotic phenotype in mice with tubule deletion of TIF1γ. Thus, tubular TIF1γ plays an important role in kidney fibrosis by suppressing profibrotic EGFR and TGF-β signaling. Hence, our findings suggest that maintaining homeostasis of tubular TIF1γ may be a new therapeutic option for treating tubulointerstitial fibrosis and subsequent CKD.
Topics: Animals; Humans; Mice; Epithelial Cells; ErbB Receptors; Fibrosis; Kidney; Mediation Analysis; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ureteral Obstruction
PubMed: 37482091
DOI: 10.1016/j.kint.2023.07.006 -
Protein & Cell Aug 2023Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their...
Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their diploid counterparts, including an increase in cell size, contributing to organ growth and tissue homeostasis, and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals. Here, we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid. Moreover, we discuss its crucial roles in cell growth and tissue regeneration in the heart, liver, and other tissues.
Topics: Humans; Liver; Hepatocytes; Cell Cycle; Polyploidy; Homeostasis
PubMed: 37526344
DOI: 10.1093/procel/pwac064 -
Seminars in Liver Disease Nov 2023The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian... (Review)
Review
The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the "ploidy conveyor," undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.
Topics: Animals; Humans; Liver Regeneration; Liver; Hepatocytes; Cell Proliferation; Polyploidy; Mammals
PubMed: 37967885
DOI: 10.1055/a-2211-2144 -
Trends in Ecology & Evolution May 2024Cold temperatures have been posited as a key driver of polyploidy (possession of multiple chromosome sets). However, high temperatures associated with fire, and the...
Cold temperatures have been posited as a key driver of polyploidy (possession of multiple chromosome sets). However, high temperatures associated with fire, and the indirect impact of post-fire environments in polypoid formation and establishment deserve more attention for a comprehensive understanding of polyploid ecology, evolution, and current distributions.
Topics: Biological Evolution; Cold Temperature; Fires; Polyploidy
PubMed: 38521739
DOI: 10.1016/j.tree.2024.02.007