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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{Auner:2013:10.1371/journal.pone.0074415,
author = {Auner, HW and Moody, AM and Ward, TH and Kraus, M and Milan, E and May, P and Chaidos, A and Driessen, C and Cenci, S and Dazzi, F and Rahemtulla, A and Apperley, JF and Karadimitris, A and Dillon, N},
doi = {10.1371/journal.pone.0074415},
journal = {PLOS One},
title = {Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells},
url = {http://dx.doi.org/10.1371/journal.pone.0074415},
volume = {8},
year = {2013}
}

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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Auner,HW
AU  - Moody,AM
AU  - Ward,TH
AU  - Kraus,M
AU  - Milan,E
AU  - May,P
AU  - Chaidos,A
AU  - Driessen,C
AU  - Cenci,S
AU  - Dazzi,F
AU  - Rahemtulla,A
AU  - Apperley,JF
AU  - Karadimitris,A
AU  - Dillon,N
DO  - 10.1371/journal.pone.0074415
PY  - 2013///
SN  - 1932-6203
TI  - Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells
T2  - PLOS One
UR  - http://dx.doi.org/10.1371/journal.pone.0074415
UR  - http://hdl.handle.net/10044/1/40673
VL  - 8
ER  -

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