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.
Results
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Journal articleBarbarulo 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: 0950-9232Regulation 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.
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Journal articleChaidos 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- Author Web Link
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- Citations: 107
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