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{O'Byrne:2019:10.1182/blood.2019001289,
author = {O'Byrne, S and Elliott, N and Rice, S and Buck, G and Fordham, N and Garnett, C and Godfrey, L and Crump, NT and Wright, G and Inglott, S and Hua, P and Psaila, B and Povinelli, B and Knapp, DJHF and Agraz-Doblas, A and Bueno, C and Varela, I and Bennett, P and Koohy, H and Watt, SM and Karadimitris, A and Mead, AJ and Ancliff, P and Vyas, P and Menendez, P and Milne, TA and Roberts, I and Roy, A},
doi = {10.1182/blood.2019001289},
journal = {Blood},
pages = {1059--1071},
title = {Discovery of a CD10 negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs},
url = {http://dx.doi.org/10.1182/blood.2019001289},
volume = {134},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Human lymphopoiesis is a dynamic life-long process that starts in utero 6 weeks post-conception. Fetal B-lymphopoiesis remains poorly defined and yet is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of two distinct CD19+ B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB- and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal BM, where together they form >40% of the total HSC/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors while, by contrast, PreProB-progenitors are almost undetectable (0.53{plus minus}0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB- upstream of ProB-progenitors, identifying them as the first B-lymphoid restricted progenitor in human fetal life. Fetal BM PreProB- and ProB-progenitors both give rise solely to B-lineage cells yet they are transcriptionally distinct. Like their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors, display a distinct, ontogeny-related gene expression pattern which is not seen in adult PreProB-progenitors; and share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid-restricted progenitor in human fetal life, and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation.
AU  - O'Byrne,S
AU  - Elliott,N
AU  - Rice,S
AU  - Buck,G
AU  - Fordham,N
AU  - Garnett,C
AU  - Godfrey,L
AU  - Crump,NT
AU  - Wright,G
AU  - Inglott,S
AU  - Hua,P
AU  - Psaila,B
AU  - Povinelli,B
AU  - Knapp,DJHF
AU  - Agraz-Doblas,A
AU  - Bueno,C
AU  - Varela,I
AU  - Bennett,P
AU  - Koohy,H
AU  - Watt,SM
AU  - Karadimitris,A
AU  - Mead,AJ
AU  - Ancliff,P
AU  - Vyas,P
AU  - Menendez,P
AU  - Milne,TA
AU  - Roberts,I
AU  - Roy,A
DO  - 10.1182/blood.2019001289
EP  - 1071
PY  - 2019///
SN  - 0006-4971
SP  - 1059
TI  - Discovery of a CD10 negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs
T2  - Blood
UR  - http://dx.doi.org/10.1182/blood.2019001289
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31383639
VL  - 134
ER  -
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