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Journal of Hematology & Oncology Sep 2020Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate...
BACKGROUND
Acute myeloid leukemia (AML) is a fatal hematopoietic malignancy and has a prognosis that varies with its genetic complexity. However, there has been no appropriate integrative analysis on the hierarchy of different AML subtypes.
METHODS
Using Microwell-seq, a high-throughput single-cell mRNA sequencing platform, we analyzed the cellular hierarchy of bone marrow samples from 40 patients and 3 healthy donors. We also used single-cell single-molecule real-time (SMRT) sequencing to investigate the clonal heterogeneity of AML cells.
RESULTS
From the integrative analysis of 191727 AML cells, we established a single-cell AML landscape and identified an AML progenitor cell cluster with novel AML markers. Patients with ribosomal protein high progenitor cells had a low remission rate. We deduced two types of AML with diverse clinical outcomes. We traced mitochondrial mutations in the AML landscape by combining Microwell-seq with SMRT sequencing. We propose the existence of a phenotypic "cancer attractor" that might help to define a common phenotype for AML progenitor cells. Finally, we explored the potential drug targets by making comparisons between the AML landscape and the Human Cell Landscape.
CONCLUSIONS
We identified a key AML progenitor cell cluster. A high ribosomal protein gene level indicates the poor prognosis. We deduced two types of AML and explored the potential drug targets. Our results suggest the existence of a cancer attractor.
Topics: Bone Marrow Examination; Cell Lineage; Clone Cells; Computer Systems; DNA, Mitochondrial; DNA, Neoplasm; Gene Expression Regulation, Leukemic; Gene Regulatory Networks; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Neoplasm Proteins; Neoplastic Stem Cells; Phenotype; Prognosis; RNA, Messenger; RNA, Neoplasm; Recurrence; Ribosomal Proteins; Single-Cell Analysis; Transcription Factors
PubMed: 32977829
DOI: 10.1186/s13045-020-00941-y -
Cell Jul 2020The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that...
The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Chromatin; Germinal Center; Histone Deacetylases; Humans; Immunologic Memory; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis, Site-Directed; Nuclear Proteins; Nuclear Receptor Co-Repressor 2; Precursor Cells, B-Lymphoid; Protein Binding; Proto-Oncogene Proteins c-bcl-6; RNA Interference; RNA, Small Interfering; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Transcription, Genetic
PubMed: 32619424
DOI: 10.1016/j.cell.2020.05.049 -
Nature Communications Feb 2022Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less...
Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers.
Topics: Female; Humans; Adaptor Proteins, Signal Transducing; Breast Neoplasms; Estrogen Receptor alpha; Hippo Signaling Pathway; Intracellular Signaling Peptides and Proteins; Phosphoproteins; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factors; YAP-Signaling Proteins
PubMed: 35217640
DOI: 10.1038/s41467-022-28691-0 -
Nature Cancer Jun 2022Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast...
Resistance to antitumor treatment contributes to patient mortality. Functional proteomic screening of organoids derived from chemotherapy-treated patients with breast cancer identified nuclear receptor corepressor 2 (NCOR2) histone deacetylase as an inhibitor of cytotoxic stress response and antitumor immunity. High NCOR2 in the tumors of patients with breast cancer predicted chemotherapy refractoriness, tumor recurrence and poor prognosis. Molecular studies revealed that NCOR2 inhibits antitumor treatment by regulating histone deacetylase 3 (HDAC3) to repress interferon regulatory factor 1 (IRF-1)-dependent gene expression and interferon (IFN) signaling. Reducing NCOR2 or impeding its epigenetic activity by modifying its interaction with HDAC3 enhanced chemotherapy responsiveness and restored antitumor immunity. An adeno-associated viral NCOR2-HDAC3 competitor potentiated chemotherapy and immune checkpoint therapy in culture and in vivo by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes to increase IFN-γ signaling. The findings illustrate the utility of patient-derived organoids for drug discovery and suggest that targeting stress and inflammatory-repressor complexes such as NCOR2-HDAC3 could overcome treatment resistance and improve the outcome of patients with cancer.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Early Detection of Cancer; Female; Humans; Neoplasm Recurrence, Local; Nuclear Receptor Co-Repressor 2; Organoids; Proteomics
PubMed: 35618935
DOI: 10.1038/s43018-022-00375-0 -
Experimental Hematology Dec 2022Over the past 2 decades, the adaptor protein transducin β-like 1 (TBL1X) and its homolog TBL1XR1 have been shown to be upregulated in solid tumors and hematologic... (Review)
Review
Over the past 2 decades, the adaptor protein transducin β-like 1 (TBL1X) and its homolog TBL1XR1 have been shown to be upregulated in solid tumors and hematologic malignancies, and their overexpression is associated with poor clinical outcomes. Moreover, dysregulation of the TBL1 family of proteins has been implicated as a key component of oncogenic prosurvival signaling, cancer progression, and metastasis. Herein, we discuss how TBL1X and TBL1XR1 are required for the regulation of major transcriptional programs through the silencing mediator for tetanoid and thyroid hormone receptor (SMRT)/nuclear receptor corepressor (NCOR)/ B cell lymphoma 6 (BCL6) complex, Wnt/β catenin, and NF-κB signaling. We outline the utilization of tegavivint (Iterion Therapeutics), a first-in-class small molecule targeting the N-terminus domain of TBL1, as a novel therapeutic strategy in preclinical models of cancer and clinically. Although most published work has focused on the transcriptional role of TBL1X, we recently showed that in diffuse large B-cell lymphoma (DLBCL), the most common lymphoma subtype, genetic knockdown of TBL1X and treatment with tegavivint resulted in decreased expression of critical (onco)-proteins in a posttranscriptional/β-catenin-independent manner by promoting their proteasomal degradation through a Skp1/Cul1/F-box (SCF)/TBL1X supercomplex and potentially through the regulation of protein synthesis. However, given that TBL1X controls multiple oncogenic signaling pathways in cancer, treatment with tegavivint may ultimately result in drug resistance, providing the rationale for combination strategies. Although many questions related to TBL1X function remain to be answered in lymphoma and other diseases, these data provide a growing body of evidence that TBL1X is a promising therapeutic target in oncology.
Topics: Humans; Carcinogenesis; NF-kappa B; Signal Transduction; Transducin; Neoplasms; Gene Expression Regulation, Neoplastic; Receptors, Cytoplasmic and Nuclear; Repressor Proteins
PubMed: 36206873
DOI: 10.1016/j.exphem.2022.09.006 -
EMBO Molecular Medicine Aug 2023Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)-positive breast cancers....
Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)-positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti-estrogens to guide treatment decision. Here, using two independent cohorts of breast cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen-sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα-positive breast tumors that could be used to enhance the response of breast cancer patients to endocrine therapy, by fostering its nuclear expression.
Topics: Humans; Female; Tamoxifen; Breast Neoplasms; Estrogen Receptor alpha; Signal Transduction; Biomarkers; Drug Resistance, Neoplasm; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Antineoplastic Agents, Hormonal; Protein-Arginine N-Methyltransferases
PubMed: 37458145
DOI: 10.15252/emmm.202217248 -
Cell Host & Microbe Jul 2021Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of...
Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of interferon-stimulated genes to reduce immune defense. Interferons upregulate numerous genes, including protein kinase R (PKR), which induce necrosome formation to activate mixed-lineage-kinase-domain-like (MLKL) pseudokinase and induce necroptosis. Whether these interferon functions are targeted by Toxoplasma is unknown. Here, we examine secreted effectors that localize to the host cell nucleus and find that the chronic bradyzoite stage secretes effector TgNSM that targets the NCoR/SMRT complex, a repressor for various transcription factors, to inhibit interferon-regulated genes involved in cell death. TgNSM acts with TgIST to block IFN-driven expression of PKR and MLKL, thus preventing host cell necroptotic death and protecting the parasite's intracellular niche. The mechanism of action of TgNSM uncovers a role of NCoR/SMRT in necroptosis, assuring survival of intracellular cysts and chronic infection.
Topics: HeLa Cells; Host-Parasite Interactions; Humans; Necroptosis; Nuclear Receptor Co-Repressor 2; Protein Kinases; Protozoan Proteins; Toxoplasma; Toxoplasmosis; eIF-2 Kinase
PubMed: 34043960
DOI: 10.1016/j.chom.2021.04.016 -
Proceedings of the National Academy of... Aug 2022Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold...
Brown adipose tissue (BAT) is a key thermogenic organ whose expression of uncoupling protein 1 (UCP1) and ability to maintain body temperature in response to acute cold exposure require histone deacetylase 3 (HDAC3). HDAC3 exists in tight association with nuclear receptor corepressors (NCoRs) NCoR1 and NCoR2 (also known as silencing mediator of retinoid and thyroid receptors [SMRT]), but the functions of NCoR1/2 in BAT have not been established. Here we report that as expected, genetic loss of NCoR1/2 in BAT (NCoR1/2 BAT-dKO) leads to loss of HDAC3 activity. In addition, HDAC3 is no longer bound at its physiological genomic sites in the absence of NCoR1/2, leading to a shared deregulation of BAT lipid metabolism between NCoR1/2 BAT-dKO and HDAC3 BAT-KO mice. Despite these commonalities, loss of NCoR1/2 in BAT does not phenocopy the cold sensitivity observed in HDAC3 BAT-KO, nor does loss of either corepressor alone. Instead, BAT lacking NCoR1/2 is inflamed, particularly with respect to the interleukin-17 axis that increases thermogenic capacity by enhancing innervation. Integration of BAT RNA sequencing and chromatin immunoprecipitation sequencing data revealed that NCoR1/2 directly regulate , which integrates extracellular matrix remodeling and inflammation. These findings reveal pleiotropic functions of the NCoR/HDAC3 corepressor complex in BAT, such that HDAC3-independent suppression of BAT inflammation counterbalances stimulation of HDAC3 activity in the control of thermogenesis.
Topics: Adipose Tissue, Brown; Animals; Histone Deacetylases; Inflammation; Mice; Mice, Knockout; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; Receptors, Retinoic Acid; Thermogenesis; Uncoupling Protein 1
PubMed: 35939699
DOI: 10.1073/pnas.2205276119 -
Cellular and Molecular Life Sciences :... Aug 2020During embryonic development, one of the two X chromosomes of a mammalian female cell is randomly inactivated by the X chromosome inactivation mechanism, which is mainly... (Review)
Review
During embryonic development, one of the two X chromosomes of a mammalian female cell is randomly inactivated by the X chromosome inactivation mechanism, which is mainly dependent on the regulation of the non-coding RNA X-inactive specific transcript at the X chromosome inactivation center. There are three proteins that are essential for X-inactive specific transcript to function properly: scaffold attachment factor-A, lamin B receptor, and SMRT- and HDAC-associated repressor protein. In addition, the absence of X-inactive specific transcript expression promotes tumor development. During the process of chromosome inactivation, some tumor suppressor genes escape inactivation of the X chromosome and thereby continue to play a role in tumor suppression. A well-functioning tumor suppressor gene on the idle X chromosome in women is one of the reasons they have a lower propensity to develop cancer than men, women thereby benefit from this enhanced tumor suppression. This review will explore the mechanism of X chromosome inactivation, discuss the relationship between X chromosome inactivation and tumorigenesis, and consider the consequent sex differences in cancer.
Topics: Chromosomes, Human, X; Humans; Mutation; Neoplasms; RNA, Long Noncoding; Sex Characteristics; Tumor Suppressor Proteins; X Chromosome Inactivation
PubMed: 32040694
DOI: 10.1007/s00018-020-03469-z -
American Journal of Clinical and... 2015Transducin (beta)-like 1X related protein 1 (TBL1XR1/TBLR1) is an integral subunit of the NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic... (Review)
Review
Transducin (beta)-like 1X related protein 1 (TBL1XR1/TBLR1) is an integral subunit of the NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) repressor complexes. It is an evolutionally conserved protein that shares high similarity across all species. TBL1XR1 is essential for transcriptional repression mediated by unliganded nuclear receptors (NRs) and othe regulated transcription factors (TFs). However, it can also act as a transcription activator through the recruitment of the ubiquitin-conjugating/19S proteasome complex that mediates the exchange of corepressors for coactivators. TBL1XR1 is required for the activation of multiple intracellular signaling pathways. TBL1XR1 germline mutations and recurrent mutations are linked to intellectual disability. Upregulation of TBL1XR1 is observed in a variety of solid tumors, which is associated with advanced tumor stage, metastasis and poor prognosis. A variety of genomic alterations, such as translocation, deletion and mutation have been identified in many types of neoplasms. Loss of TBL1XR1 in B-lymphoblastic leukemia disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance. However, the mechanisms of other types of genomic changes in tumorogenesis are still not clear. A pre-clinical study has shown that the disruption of the interaction between TBL1X and β-catenin using a small molecule can inhibit the growth of AML stem and blast cells both in vitro and in vivo. These findings shed light on the therapeutic potentials of targeting TBL1XR1 related proteins in cancer treatment.
PubMed: 26069883
DOI: No ID Found