Imperial College London

Anastasios Karadimitris

Faculty of MedicineDepartment of Immunology and Inflammation

Professor of Haematology
 
 
 
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Contact

 

+44 (0)20 3313 8438a.karadimitris

 
 
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Location

 

4S10CCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

64 results found

Rotolo A, Caputo VS, Holubova M, Baxan N, Dubois O, Chaudhry MS, Xiao X, Goudevenou K, Pitcher DS, Petevi K, Kachramanoglou C, Iles S, Naresh K, Maher J, Karadimitris Aet al., 2018, Enhanced anti-lymphoma activity of CAR19-iNKT cells underpinned by dual CD19 and CD1d targeting, Cancer Cell, Vol: 34, Pages: 596-610, 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.

Journal article

Rotolo A, Karadimitris A, Ruella M, 2018, Building upon the success of CART19: chimeric antigen receptor T cells for hematologic malignancies, LEUKEMIA & LYMPHOMA, Vol: 59, Pages: 2040-2055, ISSN: 1042-8194

Journal article

Roy A, Bystry V, Bohn G, Goudevenou K, Reigl T, Papaioannou M, Krejci A, O'Byrne S, Chaidos A, Grioni A, Darzentas N, Roberts IAG, Karadimitris Aet al., 2017, High resolution IgH repertoire analysis reveals fetal liver as the likely origin of life-long, innate B lymphopoiesis in humans, Clinical Immunology, Vol: 183, Pages: 8-16, ISSN: 1521-6616

The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM+ B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM+ B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime.

Journal article

Spanoudakis E, Papoutselis M, Terpos E, Dimopoulos MA, Tsatalas C, Margaritis D, Rahemtulla A, Kotsianidis I, Karadimitris Aet al., 2016, Overexpression of RANKL by invariant NKT cells enriched in the bone marrow of patients with multiple myeloma, BLOOD CANCER JOURNAL, Vol: 6, ISSN: 2044-5385

Journal article

Psaila B, Barkas N, Iskander D, Roy A, Anderson S, Ashley N, Caputo VS, Lichtenberg J, Loaiza S, Bodine DM, Karadimitris A, Mead AJ, Roberts Iet al., 2016, Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways, Genome Biology, Vol: 17, 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

Journal article

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.

Journal article

Karadimitris A, Chaidos A, Caputo V, Goudevenou K, Ponnusamy K, Xiao Xet al., 2015, Myeloma Propagating Cells, Drug Resistance and Relapse, STEM CELLS, Vol: 33, Pages: 3205-3211, ISSN: 1066-5099

Journal article

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

Journal article

Kleijnen MF, 2015, Bortezomib amplifies effect on intracellular proteasomes by changing proteasome structure, EBioMedicine, Vol: 2, Pages: 642-648, ISSN: 2352-3964

The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes' active-sites. MM cells are exquisitely sensitive to Bortezomib – exhibiting a low-nanomolar IC50 – suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.

Journal article

Psaltopoulou T, Sergentanis TN, Sergentanis IN, Karadimitris A, Terpos E, Dimopoulos MAet al., 2015, Alcohol intake, alcoholic beverage type and multiple myeloma risk: a meta-analysis of 26 observational studies, LEUKEMIA & LYMPHOMA, Vol: 56, Pages: 1484-1501, ISSN: 1042-8194

Journal article

Ersek A, Xu K, Antonopoulos A, Butters TD, Santo AE, Vattakuzhi Y, Williams LM, Goudevenou K, Danks L, Freidin A, Spanoudakis E, Parry S, Papaioannou M, Hatjiharissi E, Chaidos A, Alonzi DS, Twigg G, Hu M, Dwek RA, Haslam SM, Roberts I, Dell A, Rahemtulla A, Horwood NJ, Karadimitris Aet al., 2015, Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease, Journal of Clinical Investigation, Vol: 125, Pages: 2279-2292, ISSN: 1558-8238

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell–derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM.

Journal article

Iskander D, Psaila B, Gerrard G, Chaidos A, Foong HE, Harrington Y, Karnik LC, Roberts I, de la Fuente J, Karadimitris Aet al., 2015, Elucidation of the EP defect in Diamond-Blackfan anemia by characterization and prospective isolation of human EPs, BLOOD, Vol: 125, Pages: 2553-2557, ISSN: 0006-4971

Journal article

Johnston AC, Naresh K, Barwick T, May P, Karadimitris A, Auner HWet al., 2015, Cutaneous presentation of an aggressive plasmablastic neoplasm indiscriminate between lymphoma and myeloma, ANNALS OF HEMATOLOGY, Vol: 94, Pages: 691-692, ISSN: 0939-5555

Journal article

Chaudhry MS, Karadimitris A, 2014, Role and Regulation of CD1d in Normal and Pathological B Cells, JOURNAL OF IMMUNOLOGY, Vol: 193, Pages: 4761-4768, ISSN: 0022-1767

Journal article

Costa JR, Caputo VS, Makarona K, Layton DM, Roberts IAG, Almeida AM, Karadimitris Aet 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

Journal article

Naresh KN, Barwick T, Karadimitris A, 2014, IgG4 positive mucosa associated lymphoid tissue lymphoma of the orbit - lesson of the month, HISTOPATHOLOGY, Vol: 65, Pages: 718-721, ISSN: 0309-0167

Journal article

Pitcher DS, de Mattos-Shipley K, Wang Z, Tzortzis K, Goudevenou K, Flynn H, Bohn G, Rahemtulla A, Roberts I, Snijders AP, Karadimitris A, Kleijnen MFet al., 2014, Nuclear proteasomes carry a constitutive posttranslational modification which derails SDS-PAGE (but not CTAB-PAGE), Biochimica et Biophysica Acta-Proteins and Proteomics, Vol: 1844, Pages: 2222-2228, ISSN: 1570-9639

Journal article

Makarona K, Caputo VS, Costa JR, Liu B, O'Connor D, Iskander D, Roper D, Robertson L, Bhatnagar N, Terpos E, Georgiou E, Papaioannou M, Layton DM, Luzzatto L, Roberts I, Karadimitris Aet 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

Journal article

Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I, Chaudhry MS, Rotolo A, Tough DF, Smithers NN, Bassil AK, Chapman TD, Harker NR, Barbash O, Tummino P, Al-Mahdi N, Haynes AC, Cutler L, Le B, Rahemtulla A, Roberts I, Kleijnen M, Witherington JJ, Parr NJ, Prinjha RK, Karadimitris Aet al., 2014, Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762, BLOOD, Vol: 123, Pages: 697-705, ISSN: 0006-4971

Journal article

Auner HW, Moody AM, Ward TH, Kraus M, Milan E, May P, Chaidos A, Driessen C, Cenci S, Dazzi F, Rahemtulla A, Apperley JF, Karadimitris A, Dillon Net al., 2013, Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells, PLOS One, Vol: 8, ISSN: 1932-6203

Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.

Journal article

Barbarulo A, Iansante V, Chaidos A, Naresh K, Rahemtulla A, Franzoso G, Karadimitris A, Haskard DO, Papa S, Bubici Cet al., 2013, Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma, ONCOGENE, Vol: 32, Pages: 4231-4242, ISSN: 0950-9232

Journal article

Caputo VS, Costa JR, Makarona K, Georgiou E, Layton DM, Roberts I, Karadimitris Aet 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

Journal article

Gerrard G, Valgañón M, Foong HE, Kasperaviciute D, Iskander D, Game L, Müller M, Aitman TJ, Roberts I, de la Fuente J, Foroni L, Karadimitris Aet al., 2013, Target enrichment and high-throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond-Blackfan anaemia, Publisher: John Wiley & Sons Ltd., Pages: 530-536, ISSN: 0007-1048

Diamond-Blackfan anaemia (DBA) is caused by inactivating mutations in ribosomal protein (RP) genes, with mutations in 13 of the 80 RP genes accounting for 50–60% of cases. The remaining 40–50% cases may harbour mutations in one of the remaining RP genes, but the very low frequencies render conventional genetic screening as challenging. We, therefore, applied custom enrichment technology combined with high-throughput sequencing to screen all 80 RP genes. Using this approach, we identified and validated inactivating mutations in 15/17 (88%) DBA patients. Target enrichment combined with high-throughput sequencing is a robust and improved methodology for the genetic diagnosis of DBA.

Conference paper

Gerrard G, Valgañón M, Foong HE, Kasperaviciute D, Iskander D, Game L, Müller M, Aitman TJ, Roberts I, de la Fuente J, Foroni L, Karadimitris Aet al., 2013, Target enrichment and high-throughput sequencing of 80 ribosomal protein genes to identify mutations associated with Diamond-Blackfan anaemia, Br J Haematol, Pages: n/a-n/a, ISSN: 1365-2141

Diamond-Blackfan anaemia (DBA) is caused by inactivating mutations in ribosomal protein (RP) genes, with mutations in 13 of the 80 RP genes accounting for 50–60% of cases. The remaining 40–50% cases may harbour mutations in one of the remaining RP genes, but the very low frequencies render conventional genetic screening as challenging. We, therefore, applied custom enrichment technology combined with high-throughput sequencing to screen all 80 RP genes. Using this approach, we identified and validated inactivating mutations in 15/17 (88%) DBA patients. Target enrichment combined with high-throughput sequencing is a robust and improved methodology for the genetic diagnosis of DBA.

Journal article

Gargiulo L, Papaioannou M, Sica M, Talini G, Chaidos A, Richichi B, Nikolaev AV, Nativi C, Layton M, de la Fuente J, Roberts I, Luzzatto L, Notaro R, Karadimitris Aet al., 2013, Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria, BLOOD, Vol: 121, Pages: 2753-2761, ISSN: 0006-4971

Journal article

Chaidos A, Barnes CP, Cowan G, May PC, Melo V, Hatjiharissi E, Papaioannou M, Harrington H, Doolittle H, Terpos E, Dimopoulos M, Abdalla S, Yarranton H, Naresh K, Foroni L, Reid A, Rahemtulla A, Stumpf M, Roberts I, Karadimitris Aet al., 2013, Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma, BLOOD, Vol: 121, Pages: 318-328, ISSN: 0006-4971

Journal article

Sivam V, Cook L, Hughes G, Karadimitris A, Marks AJ, Matthey F, Naresh KN, Szydlo RM, Yarranton H, Kanfer EJ, Macdonald DHet al., 2012, Gemcitabine and vinorelbine chemotherapy for refractory or relapsing aggressive non-Hodgkin lymphoma, HEMATOLOGICAL ONCOLOGY, Vol: 30, Pages: 214-215, ISSN: 0278-0232

Journal article

Chaidos A, Patterson S, Szydlo R, Chaudhry MS, Dazzi F, Kanfer E, McDonald D, Marin D, Milojkovic D, Pavlu J, Davis J, Rahemtulla A, Rezvani K, Goldman J, Roberts I, Apperley J, Karadimitris Aet al., 2012, Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation, BLOOD, Vol: 119, Pages: 5030-5036, ISSN: 0006-4971

Journal article

Harris J, Ibrahim H, Amen F, Karadimitris A, Naresh KN, Macdonald DHet al., 2012, Cellular (FLICE) like inhibitory protein (cFLIP) expression in diffuse large B-cell lymphoma identifies a poor prognostic subset, but fails to predict the molecular subtype, HEMATOLOGICAL ONCOLOGY, Vol: 30, Pages: 8-12, ISSN: 0278-0232

Journal article

Murakami Y, Kanzawa N, Saito K, Krawitz PM, Mundlos S, Robinson PN, Karadimitris A, Maeda Y, Kinoshita Tet al., 2012, Mechanism for Release of Alkaline Phosphatase Caused by Glycosylphosphatidylinositol Deficiency in Patients with Hyperphosphatasia Mental Retardation Syndrome, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 6318-6325

Journal article

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