Karadimitris Lab

Contact

Anastasios Karadimitris PhD, MRCP, FRCPath

  • Professor of Haematology and Consultant Haematologist
  • Director of Centre

+44 (0)20 3313 4017
a.karadimitris@imperial.ac.uk

Areas of research

Regulatory genomics of multiple myeloma

Primary and secondary genetic events underpin the transcriptional changes that drive myeloma oncogenic transcriptional programmes. These are executed by deregulated transcription factors and chromatin binding proteins. Our aim is to understand the role of known and novel transcription factors/chromatin modifiers in the biology of multiple myeloma and discover and validate therapeutic targets.

Our experimental tools include -omics assays (ChIP-seq, ATAC-seq, RNA-seq, Capture-C), chromatin proteomics, gene editing approaches including CRISPRi and relevant in vitro and in vivo models of multiple myeloma.

Immunotherapy of multiple myeloma

The Karadimitris group have been studying the biology and therapeutic potential of invariant NKT cells (iNKT) in acute graft-versus-host disease (aGVHD) and blood cancers. They showed that donor iNKT cells protect recipients of allogeneic stem cell transplant from aGVHD and iNKT cell equipped with chimaeric antigen receptor against CD19 (CAR19-iNKT) outperform CAR19-T cells in pre-clinical models of B cell lymphoma. Following this lead, the group is now developing CAR-iNKT cell-based immunotherapy against MM that includes development and validation of CAR against established and novel targets.

Our experimental tools include short- and long term in vitro assays (including longitudinal Incucyte live-cell imaging) and xenograft animal models of blood cancers and myeloma.

In parallel to pre-clinical studies, the group are pursuing clinical development of the CAR-iNKT cell platform for blood cancers.

Citation

BibTex format

@article{Ersek:2015:10.1172/JCI59987,
author = {Ersek, A and Xu, K and Antonopoulos, A and Butters, TD and Santo, AE and Vattakuzhi, Y and Williams, LM and Goudevenou, K and Danks, L and Freidin, A and Spanoudakis, E and Parry, S and Papaioannou, M and Hatjiharissi, E and Chaidos, A and Alonzi, DS and Twigg, G and Hu, M and Dwek, RA and Haslam, SM and Roberts, I and Dell, A and Rahemtulla, A and Horwood, NJ and Karadimitris, A},
doi = {10.1172/JCI59987},
journal = {Journal of Clinical Investigation},
pages = {2279--2292},
title = {Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease},
url = {http://dx.doi.org/10.1172/JCI59987},
volume = {125},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Ersek,A
AU  - Xu,K
AU  - Antonopoulos,A
AU  - Butters,TD
AU  - Santo,AE
AU  - Vattakuzhi,Y
AU  - Williams,LM
AU  - Goudevenou,K
AU  - Danks,L
AU  - Freidin,A
AU  - Spanoudakis,E
AU  - Parry,S
AU  - Papaioannou,M
AU  - Hatjiharissi,E
AU  - Chaidos,A
AU  - Alonzi,DS
AU  - Twigg,G
AU  - Hu,M
AU  - Dwek,RA
AU  - Haslam,SM
AU  - Roberts,I
AU  - Dell,A
AU  - Rahemtulla,A
AU  - Horwood,NJ
AU  - Karadimitris,A
DO  - 10.1172/JCI59987
EP  - 2292
PY  - 2015///
SN  - 1558-8238
SP  - 2279
TI  - Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease
T2  - Journal of Clinical Investigation
UR  - http://dx.doi.org/10.1172/JCI59987
UR  - http://hdl.handle.net/10044/1/30536
VL  - 125
ER  -
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