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{Crump:2021:10.1016/j.celrep.2021.109101,
author = {Crump, NT and Hadjinicolaou, A and Xia, M and Walsby-Tickle, J and Gileadi, U and Chen, J-L and Setshedi, M and Olsen, LR and Lau, I-J and Godfrey, L and Quek, L and Yu, Z and Ballabio, E and Barnkob, MB and Napolitani, G and Salio, M and Koohy, H and Kessler, BM and Taylor, S and Vyas, P and McCullagh, JSO and Milne, TA and Cerundolo, V},
doi = {10.1016/j.celrep.2021.109101},
journal = {Cell Reports},
title = {Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation},
url = {http://dx.doi.org/10.1016/j.celrep.2021.109101},
volume = {35},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
AU  - Crump,NT
AU  - Hadjinicolaou,A
AU  - Xia,M
AU  - Walsby-Tickle,J
AU  - Gileadi,U
AU  - Chen,J-L
AU  - Setshedi,M
AU  - Olsen,LR
AU  - Lau,I-J
AU  - Godfrey,L
AU  - Quek,L
AU  - Yu,Z
AU  - Ballabio,E
AU  - Barnkob,MB
AU  - Napolitani,G
AU  - Salio,M
AU  - Koohy,H
AU  - Kessler,BM
AU  - Taylor,S
AU  - Vyas,P
AU  - McCullagh,JSO
AU  - Milne,TA
AU  - Cerundolo,V
DO  - 10.1016/j.celrep.2021.109101
PY  - 2021///
SN  - 2211-1247
TI  - Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation
T2  - Cell Reports
UR  - http://dx.doi.org/10.1016/j.celrep.2021.109101
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000649197800010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://www.sciencedirect.com/science/article/pii/S2211124721004356
VL  - 35
ER  -
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