Volume 546 Issue 7657

Editorials

A sugar high in structural biology p.186

Four Nature papers describing the receptor structures involved in glucose metabolism hold great promise for finding new ways to treat diabetes.

doi: 10.1038/546186a

News

News Features

News & Views

On the origin of our species p.212

Gaps in the fossil record have limited our understanding of how Homo sapiens evolved. The discovery in Morocco of the earliest known H. sapiens fossils might revise our ideas about human evolution in Africa. See Letters p.289 & p.293

doi: 10.1038/546212a

One ring to multiplex them all p.214

High-speed communication systems that use optical fibres often require hundreds of lasers. An approach that replaces these lasers with a single, ring-shaped optical device offers many technical advantages. See Letter p.274

doi: 10.1038/546214a

RNA repeats put a freeze on cells p.215

Droplet-like assemblies of RNA in cell nuclei are associated with certain neurodegenerative diseases. Experiments reveal that these assemblies become 'frozen' gels in cells, potentially explaining their toxicity. See Article p.243

doi: 10.1038/nature22503

Differences can hold populations together p.218

Evolution favours the body form best adapted to the local environment, but it can also favour rare forms. Stickleback experiments reveal how these two selection forces can interact, and how this can limit population divergence. See Letter p.285

doi: 10.1038/nature22502

Cracking the palaeoclimate code p.219

The geological record contains evidence of how Earth's climate responded to periodic changes in our planet's orbit and rotation. An investigation reveals how this record can be leveraged to constrain estimates of past climate dynamics.

doi: 10.1038/nature22501

Reviews

Articles

RNA phase transitions in repeat expansion disorders p.243

Nucleotide repeat expansions create templates for multivalent base-pairing, which causes RNA to undergo a sol–gel phase transition and may explain the formation of nuclear RNA foci that are commonly observed in several neurological and neuromuscular diseases.

doi: 10.1038/nature22386

Letters

The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition p.302

Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3β) activity to support MYC-controlled gene expression. BCR tumour cells exhibit increased GSK3β activity and are rescued from their competitive growth disadvantage by GSK3β inhibition. BCR lymphoma variants that restore competitive fitness normalize GSK3β activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR tumour cells.

doi: 10.1038/nature22353