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• Journal article
  Park KC, Crump NT, Louwman N, Krywawych S, Cheong YJ, Vendrell I, Gill EK, Gunadasa-Rohling M, Ford KL, Hauton D, Fournier M, Pires E, Watson L, Roseman G, Holder J, Koschinski A, Carnicer R, Curtis MK, Zaccolo M, Hulikova A, Fischer R, Kramer HB, McCullagh JSO, Trefely S, Milne TA, Swietach Pet al., 2023,

  Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation

  , Nature Cardiovascular Research, Vol: 2, Pages: 1221-1245, ISSN: 2731-0590

  Propiogenic substrates and gut bacteria produce propionate, a post-translational protein modifier. In this study, we used a mouse model of propionic acidaemia (PA) to study how disturbances to propionate metabolism result in histone modifications and changes to gene expression that affect cardiac function. Plasma propionate surrogates were raised in PA mice, but female hearts manifested more profound changes in acyl-CoAs, histone propionylation and acetylation, and transcription. These resulted in moderate diastolic dysfunction with raised diastolic Ca2+, expanded end-systolic ventricular volume and reduced stroke volume. Propionate was traced to histone H3 propionylation and caused increased acetylation genome-wide, including at promoters of Pde9a and Mme, genes related to contractile dysfunction through downscaled cGMP signaling. The less severe phenotype in male hearts correlated with β-alanine buildup. Raising β-alanine in cultured myocytes treated with propionate reduced propionyl-CoA levels, indicating a mechanistic relationship. Thus, we linked perturbed propionate metabolism to epigenetic changes that impact cardiac function.

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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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• 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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• 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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