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| Open AccessHIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease
Hypoxia inducible factor (HIF)-2α transcription factor is mutated in polycythemia and various neuroendocrine tumors. Here the authors present the crystal structure of a HIF-2α peptide bound to the pVHL-elongin B-elongin C (VBC) heterotrimeric complex and propose a classification scheme for HIF-2α mutations that helps to predict disease phenotype outcome.
- Daniel Tarade
- , Claire M. Robinson
- & Michael Ohh
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| Open AccessThe basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
Gene fusions involving MLL and different partner genes define unique subgroups of acute myelogenous leukemia, but the mechanisms underlying specific subgroups are not fully clear. Here the authors elucidate the mechanisms of MLL-AF6 induced transformation, providing a distinct pathway that involves SHARP1 as a critical target.
- Akihiko Numata
- , Hui Si Kwok
- & Daniel G. Tenen
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| Open AccessA microengineered vascularized bleeding model that integrates the principal components of hemostasis
Hemostasis is a complex ensemble of events, but current bleeding assays only analyze single components like coagulation or platelet function. Here the authors present a comprehensive vascularized microfluidic mechanical injury bleeding model that addresses different aspects of the hemostatic process.
- Yumiko Sakurai
- , Elaissa T. Hardy
- & Wilbur A. Lam
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| Open AccessPhosphatidylinositol transfer protein-α in platelets is inconsequential for thrombosis yet is utilized for tumor metastasis
Platelets support tumor metastasis formation. Here, the authors show that the phosphoinositide signaling modulated by PITPα is essential for platelet-mediated tumor metastasis signaling, but surprisingly it is dispensable in hemostasis in mice.
- Liang Zhao
- , Chelsea L. Thorsheim
- & Charles S. Abrams
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| Open AccessEditing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia
β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.
- Sachith Mettananda
- , Chris A. Fisher
- & Douglas R. Higgs
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| Open AccessClonal evolution in myelodysplastic syndromes
Myelodysplastic syndromes are a broad group of haematopoietic malignancies that often progress to acute myeloid leukaemia. Here, the authors show that linear and branched evolution occurs within myelodysplastic syndrome and these patterns can be impacted by treatment.
- Pedro da Silva-Coelho
- , Leonie I. Kroeze
- & Joop H. Jansen
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| Open AccessThe severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6
Accumulation of intermediates of haem biosynthesis, porphyrins, is harmful and usually inherited, but it is unclear how the same mutation may make some individuals more ill than others. Here, the authors show that a porphyrin transporter ABCB6 is a modulator of porphyria, and that patients with functionally defective ABCB6 show more severe symptoms.
- Yu Fukuda
- , Pak Leng Cheong
- & John D. Schuetz
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| Open AccessThe FANCD2–FANCI complex is recruited to DNA interstrand crosslinks before monoubiquitination of FANCD2
FANCD2 and FANCI are essential components of the Fanconi anaemia DNA damage repair pathway. Here the authors present the cryo-EM structure of the FANCD2-FANCI complex, providing insight into how the complex is recruited to stalled replication forks.
- Chih-Chao Liang
- , Zhuolun Li
- & Martin A. Cohn
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| Open Accessp53 downregulates the Fanconi anaemia DNA repair pathway
P53 is regarded as the guardian of the genome, however it is known that mice with increased p53 activity display characteristics of dyskeratosis congenita. Here the authors show that increased p53 activity leads to the repression of telomere maintenance and DNA repair genes.
- Sara Jaber
- , Eléonore Toufektchan
- & Franck Toledo
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| Open AccessPX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking
The molecular underpinning of autism is unclear. Here the authors show PX-RICS deficient mice exhibit autism-like social behavioural abnormalities and impaired GABAA receptor trafficking, and enhancing inhibitory synaptic transmission with a GABAAreceptor agonist ameliorate the behavioural deficits.
- Tsutomu Nakamura
- , Fumiko Arima-Yoshida
- & Tetsu Akiyama
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| Open AccessA novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51
Fanconi anaemia is an inherited disorder characterised by developmental abnormalities, bone marrow failure and predisposition to cancer. Here the authors report a de novo mutation in the DNA repair gene Rad51in an atypical subtype of Fanconi anaemia.
- Najim Ameziane
- , Patrick May
- & Josephine C. Dorsman
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| Open AccessImpaired PIEZO1 function in patients with a novel autosomal recessive congenital lymphatic dysplasia
Lukacs et al. identify mutations in the PIEZO1gene in patients with congenital lymphatic dysplasia. The study also characterizes the functional consequence of the disease-associated Piezo1 mutant proteins and show attenuated ion channel function in cellular context.
- Viktor Lukacs
- , Jayanti Mathur
- & Bryan L. Krock
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| Open AccessPlatelet actin nodules are podosome-like structures dependent on Wiskott–Aldrich syndrome protein and ARP2/3 complex
During early platelet spreading a novel F-actin structure forms, called the actin nodule. Here Poulter et al.demonstrate that actin nodule formation depends on WASp and the Arp2/3 complex, and using super-resolution microscopy they show that nodules bear a structural resemblance to podosomes.
- Natalie S. Poulter
- , Alice Y. Pollitt
- & Steven G. Thomas
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| Open AccessGenetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
Somatic mutations drive the clonal proliferation of myeloproliferative neoplasms. Here the authors conduct a genome-wide association study and identify germline variation at multiple loci associated with the development and disease phenotype of these cancers.
- William Tapper
- , Amy V. Jones
- & Nicholas C.P. Cross
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MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction
Accumulation of mitochondrial DNA (mtDNA) mutations is linked to severe anaemia by an unknown mechanism. Here the authors show that excessive mtDNA mutations impair mitochondrial expulsion during erythropoiesis leading to augmented erythrocyte clearance and anaemia in mice and humans.
- K.J. Ahlqvist
- , S. Leoncini
- & A. Suomalainen
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Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation
Increased levels of haematopoietic stem and progenitor cells in the blood have been linked to some forms of organ failure. Here, the authors show that the hormone angiotensin II increases mobilization of haematopoietic stem and progenitor cells by inducing cytoskeletal changes in bone marrow cells.
- Kyung Hee Chang
- , Ramesh C Nayak
- & Jose A Cancelas
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Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma
Protein fusions between the paracaspase MALT1 and API2 (inhibitor of apoptosis 2) are found in B-cell lymphoma. Here the authors identify the tumour suppressor LIMA1 as a new target of API2–MALT1 chimeric protein and show that API2–MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo.
- Zilin Nie
- , Ming-Qing Du
- & Kojo S. J. Elenitoba-Johnson
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| Open AccessA genome-wide association study of marginal zone lymphoma shows association to the HLA region
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
- Joseph Vijai
- , Zhaoming Wang
- & Alexandra Nieters
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum
It remains unclear why iron deficiency can protect from malaria infection. Here the authors show that iron-deficient microcytic erythrocytes are less efficiently infected by Plasmodium falciparumparasites and that iron supplementation increases the proportion of young erythrocytes more susceptible to infection.
- Martha A. Clark
- , Morgan M. Goheen
- & Carla Cerami
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| Open AccessIdentification of platelet function defects by multi-parameter assessment of thrombus formation
Platelets from patients with bleeding disorders often display altered adherence to surface proteins. In this study, de Witt et al.design a flow chamber for the systematic interrogation of platelets attaching to 52 adhesive surfaces, which may be helpful for the diagnosis of platelet disorders.
- Susanne M. de Witt
- , Frauke Swieringa
- & Judith M.E.M. Cosemans
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Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al.report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
- Guang-Hui Liu
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
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Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice
Ionizing radiation damages the gastrointestinal system, but the cell types involved in intestinal damage and repair are controversial. Here the authors use bone marrow transplantation models and various irradiation regimes to rule out a role of bone marrow-derived cells in acute gastrointestinal injury and recovery in mice.
- Brian J. Leibowitz
- , Liang Wei
- & Jian Yu
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The MHF complex senses branched DNA by binding a pair of crossover DNA duplexes
The conserved MHF1/MHF2 DNA-processing complex is essential for DNA repair in response to genotoxic stress. Here, Zhao et al.report the crystal structure of a human MHF–DNA complex that provides insight into how MHF recognizes branched DNA—a feature important for cellular resistance to DNA damage.
- Qi Zhao
- , Dorina Saro
- & Yong Xiong
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Article
| Open AccessPlatelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A
Haemophilia is a genetic bleeding disorder associated with a deficiency in the coagulation factor VIII. Here, the authors use gene therapy to achieve stable overexpression of factor VIII in platelets of dogs with haemophilia A, preventing the occurrence of severe bleeding episodes for over 2.5 years.
- Lily M. Du
- , Paquita Nurden
- & David A. Wilcox
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A mouse model of adult-onset anaemia due to erythropoietin deficiency
Kidney diseases often cause anaemia due to damage of renal erythropoietin-producing cells. Yamazaki et al. identify a new population of erythropoietin-producing cells in the renal cortex and outer medulla by establishing a mouse model for adult-onset erythropoietin-deficient anaemia.
- Shun Yamazaki
- , Tomokazu Souma
- & Masayuki Yamamoto
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Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels
Dehydrated hereditary stomatocytosis is a genetic condition in which the permeability of red blood cells to cations in increased. Albuisson and colleagues find that mutations in the mechanically-activated PIEZO1 ion channel are the major cause of the disease and result in more slowly inactivating currents.
- Juliette Albuisson
- , Swetha E Murthy
- & Ardem Patapoutian
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Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia
One of the five IL-17 receptors, IL-17RD lacks a motif thought to be required for downstream signalling. Melletet al. show that IL-17RD tunes IL-17A-dependent signalling; in its absence, MAPK signalling and neutrophil recruitment are impaired, but NF-κB activation is enhanced.
- Mark Mellett
- , Paola Atzei
- & Paul N. Moynagh
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The structure of the FANCM–MHF complex reveals physical features for functional assembly
Fanconi's anaemia is characterized by an inability to repair DNA damage and is associated with mutations in the Fanconi anaemia nuclear complex, which includes the protein FANCM. This study reports the crystal structures of a fragment of FANCM bound to the histone-fold-containing protein complex, MHF1–MHF2.
- Yuyong Tao
- , Changjiang Jin
- & Maikun Teng
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| Open AccessThe Ufm1-activating enzyme Uba5 is indispensable for erythroid differentiation in mice
Post-translational modifications are important in regulating protein function and turnover, and Ufm1 is part of a recently identified protein modification system. In this study, the authors show that Uba5, a component of the Ufm1 system, is important for regulating haematopoiesis and the differentiation of erythroid cells.
- Kanako Tatsumi
- , Harumi Yamamoto-Mukai
- & Masaaki Komatsu