BET inhibitor resistance emerges from leukaemia stem cells

Nature 525, 7570 (2015). doi:10.1038/nature14888

Authors: Chun Yew Fong, Omer Gilan, Enid Y. N. Lam, Alan F. Rubin, Sarah Ftouni, Dean Tyler, Kym Stanley, Devbarna Sinha, Paul Yeh, Jessica Morison, George Giotopoulos, Dave Lugo, Philip Jeffrey, Stanley Chun-Wei Lee, Christopher Carpenter, Richard Gregory, Robert G. Ramsay, Steven W. Lane, Omar Abdel-Wahab, Tony Kouzarides, Ricky W. Johnstone, Sarah-Jane Dawson, Brian J. P. Huntly, Rab K. Prinjha, Anthony T. Papenfuss & Mark A. Dawson

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL–AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/β-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.

Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

Nature 525, 7570 (2015). doi:10.1038/nature14898

Authors: Philipp Rathert, Mareike Roth, Tobias Neumann, Felix Muerdter, Jae-Seok Roe, Matthias Muhar, Sumit Deswal, Sabine Cerny-Reiterer, Barbara Peter, Julian Jude, Thomas Hoffmann, Łukasz M. Boryń, Elin Axelsson, Norbert Schweifer, Ulrike Tontsch-Grunt, Lukas E. Dow, Davide Gianni, Mark Pearson, Peter Valent, Alexander Stark, Norbert Kraut, Christopher R. Vakoc & Johannes Zuber

Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL–AF9;NrasG12D-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.

Parkinson's disease: Crystals of a toxic core

Nature 525, 7570 (2015). doi:10.1038/nature15630

Authors: Michel Goedert & Yifan Cheng

An ultra-high-resolution structure of the core segment of assembled α-synuclein — the protein that aggregates in the brains of patients with Parkinson's disease — has been determined. A neurobiologist and a structural biologist discuss the implications of this advance. See Article p.486

Epigenetics: The karma of oil palms

Nature 525, 7570 (2015). doi:10.1038/nature15216

Authors: Jerzy Paszkowski

Despite their clonal origin, some oil palm trees develop fruits that give almost no oil. It emerges that the number of methyl groups attached to a DNA region called Karma determine which plants are defective. See Letter p.533

Structure of the toxic core of α-synuclein from invisible crystals

Nature 525, 7570 (2015). doi:10.1038/nature15368

Authors: Jose A. Rodriguez, Magdalena I. Ivanova, Michael R. Sawaya, Duilio Cascio, Francis E. Reyes, Dan Shi, Smriti Sangwan, Elizabeth L. Guenther, Lisa M. Johnson, Meng Zhang, Lin Jiang, Mark A. Arbing, Brent L. Nannenga, Johan Hattne, Julian Whitelegge, Aaron S. Brewster, Marc Messerschmidt, Sébastien Boutet, Nicholas K. Sauter, Tamir Gonen & David S. Eisenberg

The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of

Loss of Karma transposon methylation underlies the mantled somaclonal variant of oil palm

Nature 525, 7570 (2015). doi:10.1038/nature15365

Authors: Meilina Ong-Abdullah, Jared M. Ordway, Nan Jiang, Siew-Eng Ooi, Sau-Yee Kok, Norashikin Sarpan, Nuraziyan Azimi, Ahmad Tarmizi Hashim, Zamzuri Ishak, Samsul Kamal Rosli, Fadila Ahmad Malike, Nor Azwani Abu Bakar, Marhalil Marjuni, Norziha Abdullah, Zulkifli Yaakub, Mohd Din Amiruddin, Rajanaidu Nookiah, Rajinder Singh, Eng-Ti Leslie Low, Kuang-Lim Chan, Norazah Azizi, Steven W. Smith, Blaire Bacher, Muhammad A. Budiman, Andrew Van Brunt, Corey Wischmeyer, Melissa Beil, Michael Hogan, Nathan Lakey, Chin-Ching Lim, Xaviar Arulandoo, Choo-Kien Wong, Chin-Nee Choo, Wei-Chee Wong, Yen-Yen Kwan, Sharifah Shahrul Rabiah Syed Alwee, Ravigadevi Sambanthamurthi & Robert A. Martienssen

Somaclonal variation arises in plants and animals when differentiated somatic cells are induced into a pluripotent state, but the resulting clones differ from each other and from their parents. In agriculture, somaclonal variation has hindered the micropropagation of elite hybrids and genetically modified crops, but the mechanism responsible remains unknown. The oil palm fruit ‘mantled’ abnormality is a somaclonal variant arising from tissue culture that drastically reduces yield, and has largely halted efforts to clone elite hybrids for oil production. Widely regarded as an epigenetic phenomenon, ‘mantling’ has defied explanation, but here we identify the MANTLED locus using epigenome-wide association studies of the African oil palm Elaeis guineensis. DNA hypomethylation of a LINE retrotransposon related to rice Karma, in the intron of the homeotic gene DEFICIENS, is common to all mantled clones and is associated with alternative splicing and premature termination. Dense methylation near the Karma splice site (termed the Good Karma epiallele) predicts normal fruit set, whereas hypomethylation (the Bad Karma epiallele) predicts homeotic transformation, parthenocarpy and marked loss of yield. Loss of Karma methylation and of small RNA in tissue culture contributes to the origin of mantled, while restoration in spontaneous revertants accounts for non-Mendelian inheritance. The ability to predict and cull mantling at the plantlet stage will facilitate the introduction of higher performing clones and optimize environmentally sensitive land resources.

Structure of mammalian eIF3 in the context of the 43S preinitiation complex

Nature 525, 7570 (2015). doi:10.1038/nature14891

Authors: Amedee des Georges, Vidya Dhote, Lauriane Kuhn, Christopher U. T. Hellen, Tatyana V. Pestova, Joachim Frank & Yaser Hashem

During eukaryotic translation initiation, 43S complexes, comprising a 40S ribosomal subunit, initiator transfer RNA and initiation factors (eIF) 2, 3, 1 and 1A, attach to the 5′-terminal region of messenger RNA and scan along it to the initiation codon. Scanning on structured mRNAs also requires

Crystal structures of a double-barrelled fluoride ion channel

Nature 525, 7570 (2015). doi:10.1038/nature14981

Authors: Randy B. Stockbridge, Ludmila Kolmakova-Partensky, Tania Shane, Akiko Koide, Shohei Koide, Christopher Miller & Simon Newstead

To contend with hazards posed by environmental fluoride, microorganisms export this anion through F−-specific ion channels of the Fluc family. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F− over Cl− and dual-topology dimeric assembly. To understand the chemical basis for F− permeation and how the antiparallel subunits convene to form a F−-selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F− present, to a maximum resolution of 2.1 Å. The structures reveal a surprising ‘double-barrelled’ channel architecture in which two F− ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na+. F− selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.

Corrigendum: Lanosterol reverses protein aggregation in cataracts

Nature 526, 7574 (2015). doi:10.1038/nature15253

Authors: Ling Zhao, Xiang-Jun Chen, Jie Zhu, Yi-Bo Xi, Xu Yang, Li-Dan Hu, Hong Ouyang, Sherrina H. Patel, Xin Jin, Danni Lin, Frances Wu, Ken Flagg, Huimin Cai, Gen Li, Guiqun Cao, Ying Lin, Daniel Chen, Cindy Wen, Christopher Chung, Yandong Wang, Austin Qiu, Emily Yeh, Wenqiu Wang, Xun Hu, Seanna Grob, Ruben Abagyan, Zhiguang Su, Harry Christianto Tjondro, Xi-Juan Zhao, Hongrong Luo, Rui Hou, J. Jefferson P. Perry, Weiwei Gao, Igor Kozak, David Granet, Yingrui Li, Xiaodong Sun, Jun Wang, Liangfang Zhang, Yizhi Liu, Yong-Bin Yan & Kang Zhang

Nature523, 607–611 (2015); doi:10.1038/nature14650In this Letter, author Yong-Bin Yan was incorrectly associated with affiliation number 5 (Department of Ophthalmology, Xijing Hospital) instead of affiliation number 4 (State Key Laboratory of Membrane Biology, School of Life Sciences,

Erratum: Genetic diversity and evolutionary dynamics of Ebola virus in Sierra Leone

Nature 526, 7574 (2015). doi:10.1038/nature15255

Authors: Yi-Gang Tong, Wei-Feng Shi, Di Liu, Jun Qian, Long Liang, Xiao-Chen Bo, Jun Liu, Hong-Guang Ren, Hang Fan, Ming Ni, Yang Sun, Yuan Jin, Yue Teng, Zhen Li, David Kargbo, Foday Dafae, Alex Kanu, Cheng-Chao Chen, Zhi-Heng Lan, Hui Jiang, Yang Luo, Hui-Jun Lu, Xiao-Guang Zhang, Fan Yang, Yi Hu, Yu-Xi Cao, Yong-Qiang Deng, Hao-Xiang Su, Yu Sun, Wen-Sen Liu, Zhuang Wang, Cheng-Yu Wang, Zhao-Yang Bu, Zhen-Dong Guo, Liu-Bo Zhang, Wei-Min Nie, Chang-Qing Bai, Chun-Hua Sun, Xiao-Ping An, Pei-Song Xu, Xiang-Li-Lan Zhang, Yong Huang, Zhi-Qiang Mi, Dong Yu, Hong-Wu Yao, Yong Feng, Zhi-Ping Xia, Xue-Xing Zheng, Song-Tao Yang, Bing Lu, Jia-Fu Jiang, Brima Kargbo, Fu-Chu He, George F. Gao & Wu-Chun Cao

Nature524, 93–96 (2015); doi:10.1038/nature14490This Letter should have contained an associated Creative Commons statement in the Author Information section. In addition, the Fig. 3c legend should have stated that the bar chart was adapted, with permission, from

FDA vulnerability revealed

Nature 524, 7566 (2015). doi:10.1038/524387a

A politically charged advisory committee meeting may have tipped the scales in favour of a mildly effective female libido drug.

We must build resilience into our communities

Nature 524, 7566 (2015). http://www.nature.com/doifinder/10.1038/524389a

Author: Erwann Michel-Kerjan

Innovative approaches can better equip society to deal with natural disasters and other shocks, says Erwann Michel-Kerjan.

Animal behaviour: Hummingbirds sip using mini pumps

Nature 524, 7566 (2015). doi:10.1038/524390a

Hummingbirds draw nectar into their bills using long tongues that act like tiny pumps.It was long thought that liquid travels passively up the birds' tongues without suction. But Alejandro Rico-Guevara and his colleagues at the University of Connecticut in Storrs found a different mechanism

Chemistry: Better catalyst for carbon conversion

Nature 524, 7566 (2015). doi:10.1038/524390b

A porous, crystalline compound can speed up the conversion of carbon dioxide to carbon monoxide in water.Omar Yaghi and Christopher Chang at the University of California, Berkeley, and their colleagues used structures called covalent organic frameworks (COFs) — grid-like arrangements of carbon, nitrogen and

Animal behaviour: Stinging cells help jellyfish to mate

Nature 524, 7566 (2015). doi:10.1038/524390c

Some box jellyfish display elaborate mating behaviours and even use their toxic stinging cells to ensure successful fertilization.Many jellyfish reproduce using external fertilization, but in a few box jellyfish, fertilization can occur internally. In one species (Copula sivickisi; pictured), the male

Astrophysics: Dark-energy search narrows

Nature 524, 7566 (2015). doi:10.1038/524390d

Two groups have tightened the limits on the search for elusive dark matter and dark energy, the mysterious force accelerating the expansion of the Universe.Physicists have proposed that dark energy could come from a 'chameleon' field: a force that would act in the low

Human evolution: Old finger with modern traits

Nature 524, 7566 (2015). doi:10.1038/524391a

A 1.84-million-year-old finger bone from Tanzania is the oldest known hominin hand bone with human-like features.Ancient human relatives used stone tools 2 million to 3 million years ago, but had hands that were suited to living in trees. A team led by Manuel Domínguez-Rodrigo

Atmospheric science: Carbon dioxide levels peak up high

Nature 524, 7566 (2015). doi:10.1038/524391b

The carbon dioxide concentration in Earth's upper atmosphere is increasing at more than twice the average rate observed at the surface.Jia Yue of Hampton University in Virginia and his colleagues analysed CO2 measurements at different atmospheric heights and latitudes between 2002 and

Medical microbiology: Lung pathogen evolves in isolation

Nature 524, 7566 (2015). doi:10.1038/524391c

Bacteria that infect the lungs of people with cystic fibrosis evolve into different forms in various parts of the lungs.Pradeep Singh at the University of Washington in Seattle and his team dissected the infected lungs of ten people with the disease who were having

Information technology: Suspended rods serve as bits

Nature 524, 7566 (2015). doi:10.1038/524391d

Rod-shaped nanoparticles suspended in water can store the zeroes and ones of digital computing on the basis of the rods' physical location.Most digital memories are made of solid matter. But Madhavi Krishnan at the University of Zurich in Switzerland and her colleagues stored bits