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• Conference paper
  Lee Y, Bladt F, Leonardos D, Mustafa C, Katsarou A, Atta M, Bua M, Gabriel I, Ros-Soto J, Bazeos A, Pavlu J, Loaiza S, Bray E, O'Boyle F, Nadal E, Szydlo R, Crump N, Karadimitris A, Chaidos Aet al., 2023,

  Immune graft composition is important for deepening response and outcome after autologous stem cell transplantation in patients with multiple myeloma who do not receive maintenance therapy

  , 65th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology (ASH Publications), ISSN: 0006-4971
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• Conference paper
  Ng HL, Robinson ME, Malysheva V, Deniz O, Crump N, Cosgun KN, Helian K, Spivakov M, Muschen M, Feldhahn Net al., 2023,

  The transcriptional landscape of Ph plus B-ALL Is Orchestrated by long-range enhancerpromoter interactions and the coordinated action of phosphorylation-dependent and phosphorylation-independent transcription factors

  , 65th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology (ASH Publications), ISSN: 0006-4971
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• Conference paper
  Lau J, Harman JR, Jackson NE, Denny N, Smith AL, Vyas P, Davies JO, Hughes J, Crump N, Milne TAet al., 2023,

  Sustained MYB activity Is necessary for oncogenic transcription in KMT2A-rearranged acute lymphoblastic leukemia through enhancer-promoter interactions and epigenetic modifications at enhancers

  , 65th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: American Society of Hematology (ASH Publications), ISSN: 0006-4971
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• Journal article
  Schneider P, Crump NT, Arentsen-Peters STCJM, Smith AL, Hagelaar R, Adriaanse FRS, Bos RS, de Jong A, Nierkens S, Koopmans B, Milne TA, Pieters R, Stam RWet al., 2023,

  Modelling acquired resistance to DOT1L inhibition exhibits the adaptive potential of KMT2A-rearranged acute lymphoblastic leukemia

  , Experimental Hematology & Oncology, Vol: 12, ISSN: 2162-3619

  In KMT2A-rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1+ B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/CD133, while other KMT2A::AFF1 target genes, including HOXA9 and CDK6 remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A-rearranged ALL cells upon losing dependency on one of its main oncogenic properties.

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• Journal article
  Crump NT, Smith AL, Godfrey L, Dopico-Fernandez AM, Denny N, Harman JR, Hamley JC, Jackson NE, Chahrour C, Riva S, Rice S, Kim J, Basrur V, Fermin D, Elenitoba-Johnson K, Roeder RG, Allis CD, Roberts I, Roy A, Geng H, Davies JOJ, Milne TAet al., 2023,

  MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia

  , Nature Communications, Vol: 14, Pages: 1-20, ISSN: 2041-1723

  Aberrant enhancer activation is a key mechanism driving oncogene expression in many cancers. While much is known about the regulation of larger chromosome domains in eukaryotes, the details of enhancer-promoter interactions remain poorly understood. Recent work suggests co-activators like BRD4 and Mediator have little impact on enhancer-promoter interactions. In leukemias controlled by the MLL-AF4 fusion protein, we use the ultra-high resolution technique Micro-Capture-C (MCC) to show that MLL-AF4 binding promotes broad, high-density regions of enhancer-promoter interactions at a subset of key targets. These enhancers are enriched for transcription elongation factors like PAF1C and FACT, and the loss of these factors abolishes enhancer-promoter contact. This work not only provides an additional model for how MLL-AF4 is able to drive high levels of transcription at key genes in leukemia but also suggests a more general model linking enhancer-promoter crosstalk and transcription elongation.

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