30 results found
Karadimitris A, 2021, Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma, Nature Communications, ISSN: 2041-1723
Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myelomainitiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.
Saavedra-Garcia P, Roman-Trufero M, Al-Sadah HA, et al., 2021, Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs, Proceedings of the National Academy of Sciences of USA, Vol: 118, ISSN: 0027-8424
Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known.Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stressresolution in multiple myeloma cells recovering from proteasome inhibition. Our observations definelayered and protracted programmes for stress resolution that encompass extensive changes acrossthe transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibitioninvolved protracted and dynamic changes of glucose and lipid metabolism and suppression ofmitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insultsthan acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellularresponse to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptomeanalysis pipeline, we further show that GCN2 is also a stress-independent bona fide target intranscriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus,identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumour cellsmay reveal new therapeutic targets and routes for cancer therapy optimisation.
Machuldova A, Holubova M, Caputo VS, et al., 2021, Role of Polymorphisms of NKG2D Receptor and Its Ligands in Acute Myeloid Leukemia and Human Stem Cell Transplantation, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224
Ponnusamy K, Tzioni MM, Begum M, et al., 2021, The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma., Haematologica
Multiple myeloma is a malignancy of plasma cells (PC) initiated and driven by primary and secondary genetic events. Nevertheless, myeloma PC survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B cell development in both human and mouse cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma PC, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the PC lineage-defining transcription factor IRF4, and thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a non-canonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.
Caputo VS, Trasanidis N, Xiao X, et al., 2021, Brd2/4 and Myc regulate alternative cell lineage programmes during early osteoclast differentiation in vitro, iScience, Vol: 24, Pages: 1-31, ISSN: 2589-0042
Osteoclast development in response to RANKL is critical for bone homeostasis in health and in disease. The early and direct chromatin regulatory changes imparted by the BET chromatin readers Brd2-4 and osteoclast-affiliated transcription factors (TF) during osteoclastogenesis are not known. Here, we demonstrate that in response to RANKL, early osteoclast development entails regulation of two alternative cell fate transcriptional programmes, osteoclast vs macrophage, with repression of the latter following activation of the former. Both programmes are regulated in a non-redundant manner by increased chromatin binding of Brd2 at promoters and of Brd4 at enhancers/super-enhancers. Myc, the top RANKL-induced TF, regulates osteoclast development in co-operation with Brd2/4 and Max and by establishing negative and positive regulatory loops with other lineage-affiliated TF. These insights into the transcriptional regulation of osteoclastogenesis suggest the clinical potential of selective targeting of Brd2/4 to abrogate pathological OC activation.
Iskander D, Wang G, Heuston EF, et al., 2020, Single-Cell Transcriptional Landscapes of Human Bone Marrow Reveal Distinct Erythroid Phenotypes Underpinned By Genotype in Diamond-Blackfan Anemia, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Dekojova T, Houdova L, Fatka J, et al., 2020, Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study, JOURNAL OF CLINICAL MEDICINE, Vol: 9
Barozzi I, Ostasov P, Caputo V, et al., 2020, Evolution of advanced chronic lymphoid leukemia unveiled by single-cell transcriptomics: a case report, Frontiers in Oncology, Vol: 10, ISSN: 2234-943X
Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones’ dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.
Ponnusamy K, Tzioni M-M, Begum M, et al., 2019, Novel ZBP1-IRF3 Dependency in Multiple Myeloma Mediated By IRF3-Driven Regulation of Cell Cycle Genes, BLOOD, Vol: 134, ISSN: 0006-4971
Trasanidis N, Katsarou A, Bergonia B, et al., 2019, PBX1 Co-Operates with FOXM1 to Regulate Myeloma Cell Proliferation and to Define an Ultra High-Risk chr1q Gain Myeloma Patient Subgroup, BLOOD, Vol: 134, ISSN: 0006-4971
Katsarou A, Trasanidis N, Alvarez-Benayas J, et al., 2019, Oncogenic MAF in Co-Operation with IRF4 Confers Extensive Chromatin Re-Arrangement in Plasma Cells and Generates 'Neo-Enhancers' That Regulate Genes Critical for Myeloma Biology, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Trasanidis N, Alvarez-Benayas J, Katsarou A, et al., 2019, Distinct Chromatin Accessibility Changes, Aberrant Transcription Factor Networks Combined with Novel Oncogenic Enhancers Characterise Myeloma-Initiating Genetic Events, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Saavedra-Garcia P, Al-Sadah HA, Penfold L, et al., 2019, Integrated Systems Level Examination of Proteasome Inhibitor Stress Recovery in Myeloma Cells Reveals Druggable Vulnerabilities Linked to Multiple Metabolic Processes, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Caputo VS, Trasanidis N, Xiao X, et al., 2019, Myc and Bet Proteins Orchestrate the Early Regulatory Genome Changes Required for Osteoclast Lineage Commitment, 61st Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Holubova M, Leba M, Gmucova H, et al., 2019, Improving the Clinical Application of Natural Killer Cells by Modulating Signals Signal from Target Cells, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 20
Parzych K, Saavedra Garcia P, Valbuena G, et al., 2019, The coordinated action of VCP/p97 and GCN2 regulates cancer cell metabolism and proteostasis during nutrient limitation, Oncogene, Vol: 38, Pages: 3216-3231, ISSN: 0950-9232
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing protein homoeostasis has made VCP/p97 an appealing anticancer drug target. Here, we provide evidence that VCP/p97 acts as a regulator of cellular metabolism. We found that VCP/p97 was tied to multiple metabolic processes on the gene expression level in a diverse range of cancer cell lines and in patient-derived multiple myeloma cells. Cellular VCP/p97 dependency to maintain proteostasis was increased under conditions of glucose and glutamine limitation in a range of cancer cell lines from different tissues. Moreover, glutamine depletion led to increased VCP/p97 expression, whereas VCP/p97 inhibition perturbed metabolic processes and intracellular amino acid turnover. GCN2, an amino acid-sensing kinase, attenuated stress signalling and cell death triggered by VCP/p97 inhibition and nutrient shortages and modulated ERK activation, autophagy, and glycolytic metabolite turnover. Together, our data point to an interconnected role of VCP/p97 and GCN2 in maintaining cancer cell metabolic and protein homoeostasis.
Rotolo A, Caputo VS, Holubova M, et al., 2018, Enhanced anti-lymphoma activity of CAR19-iNKT cells underpinned by dual CD19 and CD1d targeting, Cancer Cell, Vol: 34, Pages: 596-610.e11, ISSN: 1535-6108
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.
Caputo V, Goudevenou K, Trasanidis N, et al., 2017, Myeloma Cell Addiction to the Transcription Factor TCF11, 59th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Psaila B, Barkas N, Iskander D, et al., 2016, SINGLE-CELL PROFILING OF HUMAN MEGAKARYOCYTE-ERYTHROID PROGENITORS IDENTIFIES DISTINCT MEGAKARYOCYTE AND ERYTHROID DIFFERENTIATION PATHWAYS, 21st Congress of the European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 21-21, ISSN: 0390-6078
Psaila B, Barkas N, Iskander D, et al., 2016, Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways, Genome Biology, Vol: 17, Pages: 1-19, ISSN: 1474-760X
BACKGROUND: Recent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by "bulk" assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined. RESULTS: To clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlate the surface immunophenotype, transcriptional profile, and differentiation potential of individual MEP cells. Highly purified, single MEP cells were analyzed using index fluorescence-activated cell sorting and parallel targeted transcriptional profiling of the same cells was performed using a specifically designed panel of genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrate that immunophenotypic MEP comprise three distinct subpopulations: "Pre-MEP," enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity; "E-MEP," strongly biased towards erythroid differentiation; and "MK-MEP," a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally defined MEP are a mixed population, as a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally primed to generate exclusively single-lineage output. CONCLUSIONS: Our study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-de
Rotolo A, Caputo V, Karadimitris A, 2016, The prospects and promise of chimeric antigen receptor immunotherapy in multiple myeloma, British Journal of Haematology, Vol: 173, Pages: 350-364, ISSN: 1365-2141
Despite encouraging therapeutic advances, multiple myeloma (MM) remains an incurable malignancy. The exciting results of chimaeric antigen receptor (CAR)-based immunotherapy in CD19+ B-cell malignancies have spurred a great interest in extending the use of the CAR technology to other cancers, including MM.Availability of a specific, tumour-restricted antigen is crucial for the design of successful antibody-based CAR therapy. However, in MM, as in other malignancies, the relative dearth of such antigens-targets represents the main obstacle for the wider pre-clinical development and clinical application of the CAR technology.Here we provide an overview of the current progress and future promises of CAR technology in MM therapy. We highlight that, owing to its complexity, phenotypic and functional heterogeneity and the impact of the microenvironment, MM poses several challenges for CAR-based therapeutic approaches. Nevertheless, for the same reasons, MM can serve as a paradigm for better understanding, optimization and overall improvement of the CAR technology for the benefit of cancer and myeloma patients.
Karadimitris A, Chaidos A, Caputo V, et al., 2015, Myeloma Propagating Cells, Drug Resistance and Relapse, STEM CELLS, Vol: 33, Pages: 3205-3211, ISSN: 1066-5099
Psaila B, Iskander D, Mead A, et al., 2015, PROSPECTIVE ISOLATION OF NOVEL POPULATIONS OF MEGAKARYOCYTE-AND ERYTHROID-PRIMED MEGAKARYOCYTE-ERYTHROID PROGENITORS DEMONSTRATES MEGAKARYOCYTE-BIASED LINEAGE COMMITMENT IN PRIMARY MYELOFIBROSIS, 20th Congress of European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 97-97, ISSN: 0390-6078
Chaidos A, Caputo V, Karadimitris A, 2015, Inhibition of bromodomain and extraterminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence, THERAPEUTIC ADVANCES IN HEMATOLOGY, Vol: 6, Pages: 128-141, ISSN: 2040-6207
Malecová B, Caputo VS, Lee DF, et al., 2015, Taspase1 processing alters TFIIA cofactor properties in the regulation of TFIID., Transcription, Vol: 6, Pages: 21-32
TFIIA is an important positive regulator of TFIID, the primary promoter recognition factor of the basal RNA polymerase II transcription machinery. TFIIA antagonises negative TFIID regulators such as negative cofactor 2 (NC2), promotes specific binding of the TBP subunit of TFIID to TATA core promoter sequence elements and stimulates the interaction of TBP-associated factors (TAFs) in the TFIID complex with core promoter elements located downstream of TATA, such as the initiator element (INR). Metazoan TFIIA consists of 3 subunits, TFIIAα (35 kDa), β (19 kDa) and γ (12 kDa). TFIIAα and β subunits are encoded by a single gene and result from site-specific cleavage of a 55 kDa TFIIA(α/β) precursor protein by the protease Taspase1. Metazoan cells have been shown to contain variable amounts of TFIIA (55/12 kDa) and Taspase1-processed TFIIA (35/19/12 kDa) depending on cell type, suggesting distinct gene-specific roles of unprocessed and Taspase1-processed TFIIA. How precisely Taspase1 processing affects TFIIA functions is not understood. Here we report that Taspase1 processing alters TFIIA interactions with TFIID and the conformation of TFIID/TFIIA promoter complexes. We further show that Taspase1 processing induces increased sensitivity of TFIID/TFIIA complexes to the repressor NC2, which is counteracted by the presence of an INR core promoter element. Our results provide first evidence that Taspase1 processing affects TFIIA regulation of TFIID and suggest that Taspase1 processing of TFIIA is required to establish INR-selective core promoter activity in the presence of NC2.
Costa JR, Caputo VS, Makarona K, et al., 2014, Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency, BLOOD, Vol: 124, Pages: 3151-3154, ISSN: 0006-4971
Makarona K, Caputo VS, Costa JR, et al., 2014, Transcriptional and epigenetic basis for restoration of G6PD enzymatic activity in human G6PD-deficient cells, BLOOD, Vol: 124, Pages: 134-141, ISSN: 0006-4971
Chaidos A, Caputo V, Gouvedenou K, et al., 2014, Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762, BLOOD, Vol: 123, Pages: 697-705, ISSN: 0006-4971
Caputo VS, Costa JR, Makarona K, et al., 2013, Mechanism of Polycomb recruitment to CpG islands revealed by inherited disease-associated mutation, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 3187-3194, ISSN: 0964-6906
Makarona K, Caputo V, Roper D, et al., 2012, Gene-Selective Histone Hyperacetylation and Enhanced Sp1 Occupancy Underpin Transcriptional Modulation of Genes of the Glycolytic-Pentose Phosphate Pathway in Response to Histone Deacetylase Inhibitors - Therapeutic Implications, 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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