Global S&T Development Trend Analysis Platform of Resources and Environment
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.
The mid-Cretaceous period was one of the warmest intervals of the past 140 million years(1-5), driven by atmospheric carbon dioxide levels of around 1,000 parts per million by volume(6). In the near absence of proximal geological records from south of the Antarctic Circle, it is disputed whether polar ice could exist under such environmental conditions. Here we use a sedimentary sequence recovered from the West Antarctic shelf-the southernmost Cretaceous record reported so far-and show that a temperate lowland rainforest environment existed at a palaeolatitude of about 82 degrees S during the Turonian-Santonian age (92 to 83 million years ago). This record contains an intact 3-metre-long network of in situ fossil roots embedded in a mudstone matrix containing diverse pollen and spores. A climate model simulation shows that the reconstructed temperate climate at this high latitude requires a combination of both atmospheric carbon dioxide concentrations of 1,120-1,680 parts per million by volume and a vegetated land surface without major Antarctic glaciation, highlighting the important cooling effect exerted by ice albedo under high levels of atmospheric carbon dioxide.
Structurally intact tropical forests sequestered about half of the global terrestrial carbon uptake over the 1990s and early 2000s, removing about 15 per cent of anthropogenic carbon dioxide emissions(1-3). Climate-driven vegetation models typically predict that this tropical forest '
