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

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  • Journal article
    Li Y, Wilson A, Chrisochoidou Y, Martin S, Bird S, Morales S, Leiro M, Kozik Z, Crump NT, Roumeliotis TI, Choudhary J, Pawlyn Cet al., 2026,

    EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway

    , Haematologica, ISSN: 0390-6078

    Immunomodulatory agents (IMiD) and the next-generation cereblon (CRBN) E3 ligase modulators (CELMoD), targeting the IKZF1/IKZF3-IRF4-MYC axis, are effective therapies for multiple myeloma (MM) across all stages of disease. Resistance to treatment can be acquired following exposure, but a subset of patients has primary resistance, with both states necessitating the development of alternative treatment strategies. Enhancer of zeste homolog 2 (EZH2) has been shown to have increased expression at myeloma relapse and higher expression is associated with a shorter progression-free survival from diagnosis. EZH2 inhibitors have been studied as single agents in myeloma and in combination treatments to overcome drug resistance in other malignancies. In this study KMS-11 and RPMI-8226 myeloma cell lines were used as models of primary IMiD resistance, demonstrating persistent interferon regulatory factor 4 (IRF4) expression after IMiD/CELMoD exposure without loss of cell viability. The combination of tazemetostat, a Food and Drug Administration-approved EZH2 inhibitor, with IMiD/CELMoD significantly reduced IRF4 expression, induced apoptosis, and led to synergistic cell death in these resistant cell lines. Further investigations revealed that the synergistic effect of EZH2 inhibition appeared specific to IMiD/ CELMoD, was CRBN-dependent and was rescued by IRF4 overexpression. Mechanistically, tazemetostat appeared to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiD/CELMoD which also have this effect may reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.
  • Journal article
    Zhou J, Crump NT, Román-Trufero M, Auner HWet al., 2026,

    TIME-RESOLVED MULTI-LAYERED PROFILING IDENTIFIES RESOLUTION OF RIBOSOME COLLISIONS AND TRANSLATIONAL RECOVERY AS MECHANISMS CONTRIBUTING TO PROTEASOME INHIBITOR RESISTANCE

    , Haematologica, Vol: 111, Pages: 1-1, ISSN: 0390-6078

    Background. Multiple myeloma (MM) is characterised by a high dependence on intracellular protein homeostasis (proteostasis), a vulnerability exploited therapeutically by proteasome inhibitors (PIs) that disrupt protein degradation and induce proteotoxic stress. PIs have significantly improved clinical outcomes, but molecular mechanisms underlying adaptive resistance of MM cells to PI-induced stress remain incompletely understood. Ribosome collisions (RCs) are events that occur during compromised mRNA translation when ribosomes slow or pause, causing trailing ribosomes to physically collide. This triggers translational stress signaling aimed at resolving RCs and restoring homeostatic protein synthesis. Whether proteasome inhibition induces RCs in MM cells and whether RC resolution mechanisms contribute to adaptive PI resistance remains unknown. Methods. MM cell lines were exposed to a short pulse of carfilzomib (Cfz) to mimic clinical pharmacokinetics and followed by multi-omic analyses. RNA-seq and ribosome profiling (ribo-seq) were performed at 4h (acute stress), 24-48h (early recovery) and 6 days (late recovery) post-treatment. Global protein synthesis was assessed by puromycin incorporation, intracellular amino acid levels were quantified by targeted metabolomics (LC-MS/MS), and changes in gene and protein expression and phosphorylation were analysed by qRT-PCR and immunoblotting. Results. Cfz rapidly induced RCs, activation of the ZAKalpha-P38 initiated ribotoxic stress response (RSR), reduction of amino acids, activation of the integrated stress response (ISR) and suppression of global protein synthesis. Despite this translational repression, ribo-seq revealed selective enhancement of translation of proteasome subunits and stress-response genes in line with a “proteasome bounce-back” mechanism. During the 24h-48h period, RCs were resolved and both RSR and ISR signalling progressively decreased. Simultaneously, global protein synthesis recovered and
  • Conference paper
    Milne T, Smith A, Lau I-J, Denny N, Hamley J, Chahrour C, Sharp K, Elliott N, Harman J, Jackson T, Geng H, Smith O, Bond J, Roberts I, Stam R, Crump N, Davies J, Roy Aet al., 2025,

    TRANSCRIPTION ELONGATION AND ABERRANT ENHANCER ACTIVATION IN LEUKEMIA

    , Publisher: ELSEVIER SCIENCE INC, ISSN: 0301-472X
  • Journal article
    Smith AL, Denny N, Chahrour C, Sharp K, Arachi M, Dopico-Fernandez AM, Elliott N, Harman JR, Jackson T, Geng H, Smith O, Bond J, Roberts I, Stam RW, Crump NT, Davies JOJ, Roy A, Milne TAet al., 2025,

    Enhancer heterogeneity in acute lymphoblastic leukemia drives differential gene expression in patients

    , BLOOD, Vol: 146, Pages: 2073-2087, ISSN: 0006-4971
  • Journal article
    Cross JW, Field L, Smith A, Neil E, Hamer L, Jackson T, Elliott N, Rice S, Crump N, Harman J, Ling RE, Wu Q, El Ouazzani N, Thomas R, Inglott S, Bartram J, Smith O, Bond J, Roberts I, Milne TA, Roy Aet al., 2025,

    PROM1/CD133 marks a proliferative stem cell-like population of blasts in KMT2A rearranged infant ALL

    , Blood Advances, Vol: 9, Pages: 4607-4613, ISSN: 2473-9537

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