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• Journal article
  Lau I-J, Bloye G, Smith AL, Harman JR, Hamley JC, Sharlandjieva V, Denny N, Chahrour C, Li H, Jackson NE, Vyas P, Davies JOJ, Hughes JR, Crump NT, Milne TAet al., 2026,

  MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.

  , Blood, Vol: 147, Pages: 2865-2878

  Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with the significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for the nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the coactivators P300/CBP. All these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter cross talk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.

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• Journal article
  Rajhansa S, Crump NT, Khoo HM, Dopico-Fernandez A, Bozhilov Y, Brennan PE, Fedorov O, Adams C, Farnie G, Milne TA, Wilkinson ACet al., 2026,

  Inhibition of MLLT1 limits growth of KMT2A::AFF1 leukaemias without killing healthy haematopoietic stem cells

  , Experimental Hematology, Pages: 105458-105458, ISSN: 0301-472X
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• Journal article
  Ng HL, Burt R, Feldhahn N, 2026,

  BCR::ABL1-induced enhancer reprogramming uncovers hypersensitivity of Ph+ B-ALL cells to enhancer-targeting drugs

  , Advanced Science, ISSN: 2198-3844
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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

  Immunomodulatory agents (IMiDs) and the next-generation Cereblon (CRBN) E3 ligase modulators (CELMoDs), 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 have 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 a single agent in myeloma and in combination treatments to overcome drug resistance in other malignancies. In this study KMS-11 and RPMI-8226 myeloma cell lines are used as models of primary IMID resistance, demonstrating persistent Interferon regulatory factor 4 (IRF4) expression after IMiDs/CELMoDs exposure without loss of cell viability. The combination of Tazemetostat, an FDA-approved EZH2 inhibitor, with IMiDs/CELMoDs significantly reduces IRF4 expression, induces apoptosis, and leads to synergistic cell death in these resistant cell lines. Further investigations reveal that the synergistic effect of EZH2 inhibition appears specific to IMiDs/CELMoDs, is CRBN-dependent and rescued by IRF4 overexpression. Mechanistically, Tazemetostat appears to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiDs/CELMoDs 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.

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• 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

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