Condensate-Promoting ENL Mutation Drives Tumorigenesis In Vivo Through Dynamic Regulation of Histone Modifications and Gene Expression.

Gain-of-function mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment. Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.

Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia.

The chromatin reader eleven-nineteen leukemia (ENL) has been identified as a critical dependency in acute myeloid leukemia (AML), but its therapeutic potential remains unclear. We describe a potent and orally bioavailable small-molecule inhibitor of ENL, TDI-11055, which displaces ENL from chromatin by blocking its YEATS domain interaction with acylated histones. Cell lines and primary patient samples carrying MLL rearrangements or NPM1 mutations are responsive to TDI-11055. A CRISPR-Cas9-mediated mutagenesis screen uncovers an ENL mutation that confers resistance to TDI-11055, validating the compound's on-target activity. TDI-11055 treatment rapidly decreases chromatin occupancy of ENL-associated complexes and impairs transcription elongation, leading to suppression of key oncogenic gene expression programs and induction of differentiation. In vivo treatment with TDI-11055 blocks disease progression in cell line- and patient-derived xenograft models of MLL-rearranged and NPM1-mutated AML. Our results establish ENL displacement from chromatin as a promising epigenetic therapy for molecularly defined AML subsets and support the clinical translation of this approach. SIGNIFICANCE: AML is a poor-prognosis disease for which new therapeutic approaches are desperately needed. We developed an orally bioavailable inhibitor of ENL, demonstrated its potent efficacy in MLL-rearranged and NPM1-mutated AML, and determined its mechanisms of action. These biological and chemical insights will facilitate both basic research and clinical translation. This article is highlighted in the In This Issue feature, p. 2483.

A new model for quality improvement in acute inpatient psychiatry: observational data from an acute assessment unit.

OBJECTIVES: There is little research into the constituents of effective psychiatric inpatient care. The aim of this study was to assess the effectiveness of a newly adopted model of inpatient care; the acute assessment ward. DESIGN: Review of data collected over a year-long period. SETTING: Acute assessment ward in North London. PARTICIPANTS: All Admissions between 8 October 2009 and 7 October 2010. MAIN OUTCOME MEASURES: Duration of stay, need for readmission, patient satisfaction and frequency of conflict behaviours. RESULTS: A total of 485 admissions over the yearlong study period. The median stay to discharge from the assessment ward was 6 days, whereas in those transferred it was 19 days. Readmission within 28 days following discharge from the assessment ward was 13.9%, whereas those discharged from other wards was 9.2% (P = 0.1). Patient satisfaction was no lower, for all domains, than for other wards in the trust. Frequency of conflict behaviour was equal to previous studies,(1) but self harm was significantly less common (P = 0.01). CONCLUSIONS: Our data show that focusing on the 'point of entry' to inpatient services means that some admission times can be reduced without an increase in 28-day readmission rates or conflict behaviours. The acute assessment model attempts to address the need for the NHS to deliver more for less, whilst remaining focused on service-user and staff satisfaction. Research into which areas of this complex intervention are effective is challenging, but we would urge others who run services with novel structures to publish data about their functioning.