Contact

Nicholas Crump

  • Kay Kendall Intermediate Fellow

n.crump@imperial.ac.uk

Follow us on instagram (@crumplab)

Areas of Research

Epigenetic regulation of myeloma

Multiple myeloma is in many ways a disease driven by inappropriate gene expression. It is characterised by the aberrant activation of gene regulatory elements known as enhancers, stimulating the upregulation of key oncogenes. Blocking this behaviour is therefore a promising strategy for myeloma treatment, and many therapeutic strategies directly or indirectly target gene regulatory pathways.

The lab studies the epigenetic regulation of gene expression, focused on the way these processes are dysregulated in multiple myeloma. We have a particular interest in understanding the role of oncogenic enhancer activity in driving myeloma-specific transcriptional profiles, and identifying the factors responsible for this behaviour. A major goal of the lab is to identify potential therapeutic targets that could be developed as novel therapies for multiple myeloma.

We use a variety of high-throughput genomics techniques to study the chromatin landscape, including ChIP-seq, ATAC-seq and RNA-seq. We have optimised TOPmentation, a small cell-number technique that allows us to characterise the chromatin profile of myeloma patient samples. In addition, we use the 3C technology Micro-Capture-C to map the physical association of enhancers and promoters. By combining these techniques with genetic and pharmacological manipulation of myeloma cell lines, we are able to explore mechanistically enhancer function and regulation.

Mechanisms of myeloma drug resistance

Relapse is very common in myeloma after initial treatment. Patients typically enter remission following treatment, but invariably relapse, often with resistance to one or more of these drugs. There is therefore a pressing need to understand the mechanisms that drive this resistance to find ways to counteract it. We are working to identify and understand epigenetic mechanisms that drive drug resistance via changes in gene expression, which therefore may be reversed to resensitise cells to therapy.

Our team

Nick Crump (he/him)

Nick Crump (he/him)
Kay Kendall Leukaemia Fund Intermediate Fellow

Jinglin Zhou (he/him)

Jinglin Zhou (he/him)
PhD student

Jason Taslim (he/him)

Jason Taslim (he/him)
Research assistant

Sophie Ball (she/her)

Sophie Ball (she/her)
PhD student

Funders

The Kay Kendall Leukaemia Fund

Blood Cancer UK/ Matthew Wilson MM Fund

Imperial Health Charity

The Royal Society

Research Publications

Citation

BibTex format

@article{Fidyt:2022:10.1038/s41388-022-02196-y,
author = {Fidyt, K and Pastorczak, A and Cyran, J and Crump, NT and Goral, A and Madzio, J and Muchowicz, A and Poprzeczko, M and Domka, K and Komorowski, L and Winiarska, M and Harman, JR and Siudakowska, K and Graczyk-Jarzynka, A and Patkowska, E and Lech-Maranda, E and Mlynarski, W and Golab, J and Milne, TA and Firczuk, M},
doi = {10.1038/s41388-022-02196-y},
journal = {Oncogene},
pages = {1600--1609},
title = {Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax},
url = {http://dx.doi.org/10.1038/s41388-022-02196-y},
volume = {41},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The prognosis for B-cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however, lack of sufficient responses in preclinical models and the possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in a patient-derived xenograft model leads to downregulation of several tumor protein 53 (TP53)-related genes. Interestingly, auranofin, a thioredoxin reductase inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently of the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of the NOXA-encoding gene Phorbol-12-Myristate-13-Acetate-Induced Protein 1 (PMAIP1) associated with chromatin remodeling and increased transcriptional accessibility. Altogether, these results present an efficacious drug combination that could be considered for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.
AU  - Fidyt,K
AU  - Pastorczak,A
AU  - Cyran,J
AU  - Crump,NT
AU  - Goral,A
AU  - Madzio,J
AU  - Muchowicz,A
AU  - Poprzeczko,M
AU  - Domka,K
AU  - Komorowski,L
AU  - Winiarska,M
AU  - Harman,JR
AU  - Siudakowska,K
AU  - Graczyk-Jarzynka,A
AU  - Patkowska,E
AU  - Lech-Maranda,E
AU  - Mlynarski,W
AU  - Golab,J
AU  - Milne,TA
AU  - Firczuk,M
DO  - 10.1038/s41388-022-02196-y
EP  - 1609
PY  - 2022///
SN  - 0950-9232
SP  - 1600
TI  - Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax
T2  - Oncogene
UR  - http://dx.doi.org/10.1038/s41388-022-02196-y
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000749073300001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://www.nature.com/articles/s41388-022-02196-y
VL  - 41
ER  -
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