Volume 551 Number 7680



News Features

News & Views

Haze cools Pluto's atmosphere p.302

Modelling suggests that Pluto's atmospheric temperature is regulated by haze, unlike the other planetary bodies in the Solar System. The finding has implications for our understanding of exoplanetary atmospheres. See Letter p.352

doi: 10.1038/551302a

Bacteria disarm host-defence proteins p.303

Infection with Shigella flexneri bacteria is a major cause of infant death. It emerges that S. flexneri evades intracellular defences by releasing a protein that triggers the destruction of members of a key family of host enzymes. See Letter p.378

doi: 10.1038/nature24157

Ocean hotspots of nitrogen loss p.305

Microbial activity in the sea results in a loss of bioavailable nitrogen. It emerges that the climate phenomenon called the El Niño–Southern Oscillation has a surprisingly large effect on the size of this loss.

doi: 10.1038/551305a

Transgenic stem cells replace skin p.306

The treatment of a patient affected by an incurable genetic skin disease demonstrates the efficacy, feasibility and safety of replacing almost the whole skin using genetically corrected stem cells. See Letter p.327

doi: 10.1038/nature24753

The buoyancy of Earth's deep mantle p.308

The physical nature of two regions called large low-shear-velocity provinces at the base of Earth's mantle is uncertain. A measurement of their density has implications for our understanding of mantle dynamics. See Article p.321

doi: 10.1038/551308a

The effect of conservation spending p.309

Statistical analysis of data on threatened species provides a model that can predict how rates of investment in conservation affect biodiversity under changing human population levels and agricultural and economic conditions. See Letter p.364

doi: 10.1038/nature24158

A broadly protective antibody p.310

A single antibody uses multiple antiviral mechanisms to block the replication of influenza B viruses in mice and ferrets. The development could inform research into improved flu vaccines.

doi: 10.1038/551310a



Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity p.340

IgA+ B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8+ T cells.

doi: 10.1038/nature24302


BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation p.384

The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mut AML. Gene sets characteristic for IDHmut AML were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1high AML showed robust enrichment for leukaemia stem-cell signatures, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA–BCAT1–αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.

doi: 10.1038/nature24294