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The epigenetic cofactor ENL (eleven-nineteen-leukemia) and the acetyltransferase MOZ (monocytic leukemia zinc finger) have vital roles in transcriptional regulation and are implicated in aggressive forms of leukemia. Here, we describe the mechanistic basis for the intertwined association of ENL and MOZ. Genomic analysis shows that ENL and MOZ co-occupy active promoters and that MOZ recruits ENL to its gene targets. Structural studies reveal a multivalent assembly of ENL at the intrinsically disordered region (IDR) of MOZ. While the extraterminal (ET) domain of ENL recognizes the canonical ET-binding motif in IDR, the YEATS domains of ENL and homologous AF9 bind to a set of acetylation sites in the MOZ IDR that are generated by the acetyltransferase CBP (CREB-binding protein). Our findings suggest a multifaceted acetylation-dependent and independent coupling of ENL, MOZ and CBP/p300, which may contribute to leukemogenic activities of the ENL–MOZ assembly and chromosomal translocations of ENL, MOZ and CBP/p300.

ObjectiveColorectal cancer (CRC) is a leading cause of cancer-related deaths, with the majority of cases initiated by inactivation of the APC tumour suppressor. This results in the constitutive activation of canonical WNT pathway transcriptional effector ß-catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM which antagonises WNT-FZD receptor-ligand interactions. Here, we sought to evaluate the effects of NOTUM activity on CRC as a function of driver mutation landscape.DesignMouse and human colon organoids engineered with combinations of CRC driver mutations were used for Notum genetic gain-of-function and loss-of-function studies. In vitro assays, in vivo endoscope-guided orthotopic organoid implantation assays and transcriptomic profiling were employed to characterise the effects of Notum activity. Small molecule inhibitors of Notum activity were used in preclinical therapeutic proof-of-principle studies targeting oncogenic Notum activity.ResultsNOTUM retains tumour suppressive activity in APC-null adenomas despite constitutive ß-catenin activity. Strikingly, on progression to adenocarcinoma with P53 loss, NOTUM becomes an obligate oncogene. These phenotypes are Wnt-independent, resulting from differential activity of NOTUM on glypican 1 and 4 in early-stage versus late-stage disease, respectively. Ultimately, preclinical mouse models and human organoid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonisation of distal organs.ConclusionsOur findings that a single agent targeting the extracellular enzyme NOTUM is effective in treating highly aggressive, metastatic adenocarcinomas in preclinical mouse models and human organoids make NOTUM and its glypican targets therapeutic vulnerabilities in advanced CRC.

Small intestine transplantation is the only life-saving therapy available for patients with intestinal failure and life-threatening complications of parenteral nutrition, but it is still plagued by high levels of early acute rejection. The ability to diagnose rejection noninvasively, ideally before pathologic manifestations, would be a major advance in the care of intestinal transplant patients.

We used an experimental procedure based on a mathematical epidemiology model to compare the transmission, virulence, and recovery coefficients of Litopenaeus vannamei(Kona stock) exposed to white spot syndrome virus (WSSV) or Taura syndrome virus (TSV). The procedure involved exposing 12 susceptible shrimp to a single WSSV- or TSV-infected shrimp cadaver for 14 h and then isolating the exposed shrimp individually for 5 d to determine the number of infections and deaths. The L. vannameiused in the experiments were from the original unselected, highly susceptible population of shrimp maintained by the U.S. Marine Shrimp Farming Program. Two experiments were conducted, the results from which were similar. The estimated transmission coefficients were 0.61 for the TSV exposures and 0.41 for the WSSV exposures. The estimated virulence coefficient was higher for the WSSV exposures (0.37) than for the TSV exposures (0.12). In contrast, the estimated recovery coefficient was higher for the TSV exposures (0.10) than for the WSSV exposures (0). For the WSSV-exposed shrimp, most animals died 24–48 h postexposure; for the TSV-exposed shrimp, most died 48–96 h postexposure.