Publications
81 results found
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
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- Citations: 28
Costa JR, Caputo VS, Makarona K, et al., 2014, Cell-type-specific transcriptional regulation of <i>PIGM</i> underpins the divergent hematologic phenotype in inherited GPl deficiency, BLOOD, Vol: 124, Pages: 3151-3154, ISSN: 0006-4971
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- Citations: 2
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
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- Citations: 9
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
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- Citations: 17
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
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- Citations: 154
Pitcher DS, De Mattos-Shipley K, Wang Z, et 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
We report that subunits of human nuclear proteasomes carry a previously unrecognised, constitutive posttranslational modification. Subunits with this modification are not visualised by SDS-PAGE, which is used in almost all denaturing protein gel electrophoresis. In contrast, CTAB-PAGE readily visualises such modified subunits. Thus, under most experimental conditions, with identical samples, SDS-PAGE yielded gel electrophoresis patterns for subunits of nuclear proteasomes which were misleading and strikingly different from those obtained with CTAB-PAGE. Initial analysis indicates a novel modification of a high negative charge with some similarity to polyADP-ribose, possibly explaining compatibility with (positively-charged) CTAB-PAGE but not (negatively-charged) SDS-PAGE and providing a mechanism for how nuclear proteasomes may interact with chromatin, DNA and other nuclear components.
Auner HW, Moody AM, Ward TH, et 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.
Barbarulo A, Iansante V, Chaidos A, et 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
Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.
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
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- Citations: 8
Gerrard G, Valgañón M, Foong HE, et 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.
Gerrard G, Valgañón M, Foong HE, et 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.
Gargiulo L, Papaioannou M, Sica M, et al., 2013, Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria, BLOOD, Vol: 121, Pages: 2753-2761, ISSN: 0006-4971
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- Citations: 64
Chaidos A, Barnes CP, Cowan G, et 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
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- Citations: 107
Sivam V, Cook L, Hughes G, et al., 2012, Gemcitabine and vinorelbine chemotherapy for refractory or relapsing aggressive non-Hodgkin lymphoma, HEMATOLOGICAL ONCOLOGY, Vol: 30, Pages: 214-215, ISSN: 0278-0232
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- Citations: 2
Chaidos A, Patterson S, Szydlo R, et 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
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- Citations: 110
Harris J, Ibrahim H, Amen F, et 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
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- Citations: 3
Murakami Y, Kanzawa N, Saito K, et 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
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- Citations: 72
Ersek A, Karadimitris A, Horwood NJ, 2012, Effect of glycosphingolipids on osteoclastogenesis and osteolytic bone diseases., Front Endocrinol (Lausanne), Vol: 3
Alterations in glycosphingolipid (GSL) production results in lysosomal storage disorders associated with neurodegenerative changes. In Gaucher's disease, the patients also develop osteoporosis that is ameliorated upon treatment for the underlying defect in GSL metabolism. The role of GSLs in osteoclast and osteoblast formation is discussed here as well as the potential therapeutic uses of already approved drugs that limit GSL production in bone loss disorders such as multiple myeloma and periodontal disease.
Karadimitris A, Chaidos A, 2012, The Role of Invariant NKT Cells in Allogeneic Hematopoietic Stem Cell Transplantation, CRITICAL REVIEWS IN IMMUNOLOGY, Vol: 32, Pages: 157-171, ISSN: 1040-8401
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- Citations: 6
Roy A, Cowan G, Mead AJ, et al., 2012, Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21., Proceedings of the National Academy of Sciences
Kotsianidis I, Nakou E, Spanoudakis E, et al., 2011, The Diagnostic Value of CD1d Expression in a Large Cohort of Patients With B-Cell Chronic Lymphoproliferative Disorders, AMERICAN JOURNAL OF CLINICAL PATHOLOGY, Vol: 136, Pages: 400-408, ISSN: 0002-9173
Hu M, Bassett JHD, Danks L, et al., 2011, Activated Invariant NKT Cells Regulate Osteoclast Development and Function, JOURNAL OF IMMUNOLOGY, Vol: 186, Pages: 2910-2917, ISSN: 0022-1767
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- Citations: 32
Georgiou E, Layton M, Karadimitris A, 2009, Inherited GPI Deficiency: A Disorder of Histone Hypoacetylation, BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS, Vol: 87, Pages: 327-334, ISSN: 1542-975X
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- Citations: 2
Almeida A, Layton M, Karadimitris A, 2009, Inherited glycosylphosphatidyl inositol deficiency: A treatable CDG, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, Vol: 1792, Pages: 874-880, ISSN: 0925-4439
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- Citations: 32
Kotsianidis I, Bouchliou I, Nakou E, et al., 2009, Kinetics, function and bone marrow trafficking of CD4<SUP>+</SUP>CD25<SUP>+</SUP>FOXP3<SUP>+</SUP> regulatory T cells in myelodysplasticsyndromes (MDS), LEUKEMIA, Vol: 23, Pages: 510-518, ISSN: 0887-6924
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- Citations: 109
Spanoudakis E, Hu M, Naresh K, et al., 2009, Regulation of multiple myeloma survival and progression by CD1d, Blood, Vol: 113, Pages: 2498-2507-2498-2507
Down-regulation of conventional human leukocyte antigen (HLA) class I and II molecules from the surface of tumor cells is an important mechanism for tumor immune evasion, survival, and progression. Whether CD1d, a nonconventional, glycolipid-presenting HLA class I–like molecule instructing the function of the immunoregulatory invariant NKT cells can affect tumor cell survival is not known. Here we show that CD1d is highly expressed in premalignant and early myeloma, but with disease progression its expression is reduced and eventually in advanced stages and myeloma cell lines is lost altogether, suggesting that CD1d impacts negatively on myeloma cell survival. Consistent with this, engagement of CD1d by anti-CD1d monoclonal antibodies (mAbs) induces cell death of myeloma cell lines with restored CD1d expression and primary myeloma cells. Cell death induced by monoclonal antibody engagement of CD1d is associated with overexpression of proapoptotic Bax and mitochondrial membrane potential loss but it is caspase-activation independent; in addition, it requires the cytoplasmic tail but not the Tyr residue critical for lysosomal sorting of CD1d. Finally, anti-CD1d cooperates with antimyeloma agents in the killing of myeloma cells. Thus, this work provides evidence linking a novel function of CD1d in the regulation of cell death with tumor survival and progression in humans.
Tunstall-Pedoe O, Roy A, Karadimitris A, et al., 2008, Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of <i>GATA1</i> mutations, BLOOD, Vol: 112, Pages: 4507-4511, ISSN: 0006-4971
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- Citations: 106
Patterson S, Chaidos A, Neville DCA, et al., 2008, Human invariant NKT cells display by invariant TCR-CD1d interaction receptors, JOURNAL OF IMMUNOLOGY, Vol: 181, Pages: 3268-3276, ISSN: 0022-1767
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- Citations: 21
Patterson S, Chaidos A, Neville DCA, et al., 2008, Human invariant NKT cells display alloreactivity instructed by invariant TCR-CD1d interaction and killer Ig receptors., J Immunol, Vol: 181, Pages: 3268-3276
Invariant NKT (iNKT) cells are a subset of highly conserved immunoregulatory T cells that modify a variety of immune responses, including alloreactivity. Central to their function is the interaction of the invariant TCR with glycosphingolipid (GSL) ligands presented by the nonpolymorphic MHC class I molecule CD1d and their ability to secrete rapidly large amounts of immunomodulatory cytokines when activated. Whether iNKT cells, like NK and conventional T cells, can directly display alloreactivity is not known. We show in this study that human iNKT cells and APC can establish a direct cross-talk leading to preferential maturation of allogeneic APC and a considerably higher reactivity of iNKT cells cultured with allogeneic rather that autologous APC. Although the allogeneic activation of iNKT cells is invariant TCR-CD1d interaction-dependent, GSL profiling suggests it does not involve the recognition of disparate CD1d/GSL complexes. Instead, we show that contrary to previous reports, iNKT cells, like NK and T cells, express killer Ig receptors at a frequency similar to that of conventional T cells and that iNKT cell allogeneic activation requires up-regulation and function of activating killer Ig receptors. Thus, iNKT cells can display alloreactivity, for which they use mechanisms characteristic of both NK and conventional T cells.
Almeida AM, Murakami Y, Baker A, et al., 2007, Brief report: Targeted therapy for inherited GPI deficiency., NEW ENGLAND JOURNAL OF MEDICINE, Vol: 356, Pages: 1641-1647, ISSN: 0028-4793
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- Citations: 67
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