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Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

Cyclohexene isotopologues and stereoisotopomers with varying degrees of deuteration are formed by binding a tungsten complex to benzene, which facilitates the selective incorporation of deuterium into any position on the ring.

State-of-the-art optical clocks(1) achieve precisions of 10(-18) or better using ensembles of atoms in optical lattices(2,3) or individual ions in radio-frequency traps(4,5). Promising candidates for use in atomic clocks are highly charged ions(6) (HCIs) and nuclear transitions(7), which are largely insensitive to external perturbations and reach wavelengths beyond the optical range(8) that are accessible to frequency combs(9). However, insufficiently accurate atomic structure calculations hinder the identification of suitable transitions in HCIs. Here we report the observation of a long-lived metastable electronic state in an HCI by measuring the mass difference between the ground and excited states in rhenium, providing a non-destructive, direct determination of an electronic excitation energy. The result is in agreement with advanced calculations. We use the high-precision Penning trap mass spectrometer PENTATRAP to measure the cyclotron frequency ratio of the ground state to the metastable state of the ion with a precision of 10(-11)-an improvement by a factor of ten compared with previous measurements(10,11). With a lifetime of about 130 days, the potential soft-X-ray frequency reference at 4.96 x 10(16) hertz (corresponding to a transition energy of 202 electronvolts) has a linewidth of only 5 x 10(-8) hertz and one of the highest electronic quality factors (10(24)) measured experimentally so far. The low uncertainty of our method will enable searches for further soft-X-ray clock transitions(8,12) in HCIs, which are required for precision studies of fundamental physics(6).

Penning trap mass spectrometry is used to measure the electronic transition energy from a long-lived metastable state to the ground state in highly charged rhenium ions with a precision of 10(-11).

Plants are essential for life and are extremely diverse organisms with unique molecular capabilities(1). Here we present a quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana. Our analysis provides initial answers to how many genes exist as proteins (more than 18,000), where they are expressed, in which approximate quantities (a dynamic range of more than six orders of magnitude) and to what extent they are phosphorylated (over 43,000 sites). We present examples of how the data may be used, such as to discover proteins that are translated from short open-reading frames, to uncover sequence motifs that are involved in the regulation of protein production, and to identify tissue-specific protein complexes or phosphorylation-mediated signalling events. Interactive access to this resource for the plant community is provided by the ProteomicsDB and ATHENA databases, which include powerful bioinformatics tools to explore and characterize Arabidopsis proteins, their modifications and interactions.

A quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana provides a valuable resource for plant research.