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| Open AccessTHZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors
T-cell lymphomas are aggressive diseases associated with poor outcome. Here, the authors show that the THZ1, a CDK7 inhibitor, suppresses STAT transcriptional activity leading to apoptosis and sensitization to BCL2 inhibitors in T-cell lymphomas.
- Florencia Cayrol
- , Pannee Praditsuktavorn
- & Leandro Cerchietti
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Article
| Open AccessMutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome
Spliceosome mutations occur in approximately 50% of patients with myelodysplastic syndromes. Here, the authors show that tumour cells harbouring theS34F mutation in the U2AFspliceosome gene is sensitive to compounds that further perturb the spliceosome.
- Cara Lunn Shirai
- , Brian S. White
- & Matthew J. Walter
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Article
| Open AccessEvolution of multiple cell clones over a 29-year period of a CLL patient
Studying the genetic progression of many cancers is difficult as longitudinal samples are rarely available. Here, the authors analyse a patient with chronic lymphocytic leukaemia over a 29 year period and track the clonal evolution of the patient’s disease and response to therapy.
- Zhikun Zhao
- , Lynn Goldin
- & Michael Dean
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Article
| Open AccessMultiple myeloma risk variant at 7p15.3 creates an IRF4-binding site and interferes with CDCA7L expression
Genome wide association studies have identified multiple risk loci for multiple myeloma. Here, the authors show that the expression of CDCA7Lis associated with patient survival and expression of the gene is influenced by a risk variant at 7p15.3, which creates a transcription factor binding site for IRF4.
- Ni Li
- , David C. Johnson
- & Richard S. Houlston
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Article
| Open AccessGenomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
- Zhaohui Gu
- , Michelle Churchman
- & Charles G. Mullighan
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Article
| Open AccessType II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations
Enteropathy associated T-cell lymphoma -EATL- affects the intestine and there are two different subtypes. In this study, the authors carry out exome sequencing of the type II variant and find that it is characterized by recurrent mutations in the histone methyltransferase SETD2 that are accompanied by altered H3K6 methylation.
- Annalisa Roberti
- , Maria Pamela Dobay
- & Laurence de Leval
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Article
| Open AccessORP4L is essential for T-cell acute lymphoblastic leukemia cell survival
Lymphocytic leukaemia cells are characterized by high respiratory rates. Here, the authors report that the oxysterol-binding protein ORPL4 sustains mitochondrial respiration in T-cell acute lymphoblastic leukaemia cells by regulating Ca2+release from the endoplasmic reticulum.
- Wenbin Zhong
- , Qing Yi
- & Daoguang Yan
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Article
| Open AccessSynergistic effects of ion transporter and MAP kinase pathway inhibitors in melanoma
Treatment responses of melanoma patients to MAPK pathway inhibitors are often limited. Here, the authors show that combining cardiac glycosides with MAPK inhibitors improves tumor regression by inducing intracellular acidification, mitochondrial calcium dysregulation, ATP depletion, and cell death.
- Ugur Eskiocak
- , Vijayashree Ramesh
- & Sean J. Morrison
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Article
| Open AccessClonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults
Clonal haematopoiesis has been thought to occur in less than 10% of individuals younger than 70 years old. Here, the authors use an error corrected next-generation sequencing method to find clonal haematopoiesis in the peripheral blood of 19 of 20 healthy 50–70 year old individuals.
- Andrew L. Young
- , Grant A. Challen
- & Todd E. Druley
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Article
| Open AccessGenetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia
Pre-leukaemic clones, together with the propensity to cause disease in mice, are characterized by appearing early in myeloid leukaemia and being found at relapse. Here, the authors identify clones in human samples and find that they are characterized by hierarchically organized genetic lesions, which can be used to track evolution of the disease.
- Pierre Hirsch
- , Yanyan Zhang
- & François Delhommeau
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Article
| Open AccessCD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
CAR-T targeting CD19 have been successfully used in a variety of B-cell malignancies but patients may eventually relapse. Here, the authors show that CD19 CAR-T resistance in pre-B cell ALL can be due to the induction of a myeloid lineage switch through an epigenetic alterations in master regulators of B cell development.
- Elad Jacoby
- , Sang M. Nguyen
- & Terry J. Fry
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Article
| Open AccessLeukaemia cell of origin identified by chromatin landscape of bulk tumour cells
A tumour’s cell of origin may influence tumour progression and response to therapy. Here, the authors demonstrate that the cell of origin determines the aggressiveness of AML in a mouse model and identify unique biomarkers of the specific leukaemia cell of origin by profiling open chromatin regions of AML samples.
- Joshy George
- , Asli Uyar
- & Jennifer J. Trowbridge
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Article
| Open AccessGenome-wide association study identifies multiple susceptibility loci for multiple myeloma
Previous genome-wide association studies have identified loci associated with the risk of multiple myeloma. Here, the authors present a meta-analysis of six genome wide association studies of the disease and identify eight new loci; functional studies identify genes as candidates for the basis of these associations.
- Jonathan S. Mitchell
- , Ni Li
- & Richard S. Houlston
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Article
| Open AccessChromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks
Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity. Here, the authors report the genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using ATAC-seq, and 10 matched RNA-seq datasets, providing a resource for studying epigenome deregulation in CLL.
- André F. Rendeiro
- , Christian Schmidl
- & Christoph Bock
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Article
| Open AccessA threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
NFATc1 orchestrates thymocyte development. Here the authors show that NFATc1 expression is regulated by distinct promoters during thymocyte differentiation, and by conditional deletion of individual promoters in mice they define their specific roles in the control of T-cell development by NFATc1.
- Stefan Klein-Hessling
- , Ronald Rudolf
- & Amiya Kumar Patra
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Article
| Open AccessIdentification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
The fusion of two genes during the pathogenesis of cancer can create oncogenes. In this study, the authors screen pediatric B-cell precursor acute lymphoblastic leukaemia samples for the presence of fusion genes and describe fusion genes that define new molecular subtypes of the disease
- Henrik Lilljebjörn
- , Rasmus Henningsson
- & Thoas Fioretos
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Article
| Open AccessZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation
The t(8;21) translocation is often found in acute myeloid leukaemia but is not sufficient for development of the disease. In this study, the authors identify frequent mutations in the transcriptional repressor, ZBTB7A, in these patients and show that the mutations reduce DNA binding activity.
- Luise Hartmann
- , Sayantanee Dutta
- & Philipp A. Greif
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Article
| Open AccessClonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition
The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.
- Jan A. Burger
- , Dan A. Landau
- & Catherine J. Wu
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Article
| Open AccessmiR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia
Mir-22 has been shown to be an oncogenic microRNA in breast cancer and myelodysplastic syndrome. Here, the authors show that mir-22 functions as a tumour suppressor in de novoacute myeloid leukaemia by inhibiting the expression of several oncogenes and that restoring mir-22 expression suppresses AML progression.
- Xi Jiang
- , Chao Hu
- & Jianjun Chen
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Article
| Open AccessRepression of GSK3 restores NK cell cytotoxicity in AML patients
Natural killer cells of acute myeloid leukaemia patients lack cytotoxic activity. Here the authors show that these cells have elevated GSK3β, and that its inhibition prolongs survival of mice transplanted with human AML and stimulates NK cytotoxicity via increased adhesion of NK cells to their targets.
- Reshmi Parameswaran
- , Parameswaran Ramakrishnan
- & David N. Wald
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Article
| Open AccessDNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation
DNMT3A mutations are known to cause acute myeloid leukaemia. Here, Koya et al. show that DNMT3A R882H mutation causes monoblastic transformation and haematopoietic stem cell accumulation in a methylation-independent manner, by suppressing the polycomb repressive complex 1, causing transcriptional silencing.
- Junji Koya
- , Keisuke Kataoka
- & Mineo Kurokawa
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Article
| Open AccessAcetylation of C/EBPα inhibits its granulopoietic function
C/EBPα is an essential transcription factor for myeloid lineage commitment. Here, the authors show that acetylation of C/EBPα at K298 and K302, mediated at least in part by GCN5, impairs C/EBPα DNA binding ability and modulates C/EBPα transcriptional activity.
- Deepak Bararia
- , Hui Si Kwok
- & Daniel G. Tenen
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Article
| Open AccessMeta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPPassociated with risk of this disease.
- Sonja I. Berndt
- , Nicola J. Camp
- & Susan L. Slager
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Article
| Open AccessMutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents
Chronic myelomonocytic leukaemia is treated with agents that modify DNA methylation but whether they have direct cytotoxic effects is unclear. Here, the authors show that cells from treated patients show marked methylation changes without altered somatic mutation burden, suggesting that cytotoxicity is not a major factor in therapeutic efficacy.
- Jane Merlevede
- , Nathalie Droin
- & Eric Solary
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Article
| Open AccessMSI2 is required for maintaining activated myelodysplastic syndrome stem cells
Several studies have recently demonstrated the role of the MSI2 RNA binding protein in normal and malignant haematopoietc stem cells. In this study, the authors show that MSI2 is required for maintaining myelodysplastic syndrome stem cells in mice and that MSI2 expression predicts poor prognosis in patients affected by this disease.
- James Taggart
- , Tzu-Chieh Ho
- & Michael G. Kharas
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Article
| Open AccessA variant at 9p21.3 functionally implicates CDKN2B in paediatric B-cell precursor acute lymphoblastic leukaemia aetiology
A risk variant located at 9p21.3 is associated with cancer risk in pediatric B-cell precursor acute lymphoblastic leukaemia. Here, the authors show that this variant affects the gene expression of the tumour suppressor gene Cdkn2b.
- Eric A. Hungate
- , Sapana R. Vora
- & Kenan Onel
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Article
| Open AccessAnaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress
Anaplastic large cell lymphoma is characterized by an NPM–ALK fusion but the cell of origin for this cancer is unclear. Here, the authors show that, in an NPM–ALK mouse model, the tumours likely arise from early thmyocytes and require an initial burst of TCR signalling for initiation.
- Tim I. M. Malcolm
- , Patrick Villarese
- & Suzanne D. Turner
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Article
| Open AccessGenome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma
The prognosis of multiple myeloma patients varies widely. Here, to identify genetic factors associated with differing prognoses, the authors carried out a meta-analysis of four genome-wide association studies and identified a risk variant associated with survival interval.
- David C. Johnson
- , Niels Weinhold
- & Gareth J. Morgan
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Article
| Open AccessThe KDM3A–KLF2–IRF4 axis maintains myeloma cell survival
Several histone modifiers have been implicated in the survival of multiple myeloma cells. Here, the authors reveal a role for the histone demethylase KDM3A in the survival of this haematologic cancer, and show that mechanistically KDM3A removes H3K9 methylation from the promoters of KLF2 and IRF4, genes essential for myeloma cell survival.
- Hiroto Ohguchi
- , Teru Hideshima
- & Kenneth C. Anderson
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Article
| Open AccessSF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.
- Syed A. Mian
- , Kevin Rouault-Pierre
- & Ghulam J. Mufti
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Article
| Open AccessWhole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
The oncogenic events driving indolent chronic lymphocytic leukaemia are relatively unknown. Here, the authors perform whole genome sequencing on 30 such tumours and identify recurrent mutations in IGLL5and two activation induced cytidine deaminase signatures that are operative at different stages of CLL evolution.
- S. Kasar
- , J. Kim
- & J. R. Brown
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Article
| Open AccessOsteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche
Therapy resistant dormant myeloma cells contribute to disease relapse. Here, the authors use intravital microscopy to track the location of these cells and demonstrate that they hone to the endosteal niche within the bone.
- Michelle A. Lawson
- , Michelle M. McDonald
- & Peter I. Croucher
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Article
| Open AccessAcute loss of TET function results in aggressive myeloid cancer in mice
TET dioxygenases are known to have tumour suppressor activity. Here, An et al. show that Tet2/Tet3 double conditional mutant mice develop aggressive myeloid leukaemia, and suggest that rather than increased DNA methylation, aberrant gene expression and defects in DNA damage response and repair are the major drivers of myeloid leukaemogenesis upon TET loss-of-function.
- Jungeun An
- , Edahí González-Avalos
- & Anjana Rao
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Article
| Open AccessWhole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes
The molecular events that drive the disease progression of myelodysplastic syndromes are poorly understood. Here, the authors report the identification of novel progression-related somatic mutations in ROBO1 and ROBO2, highlighting ROBO-SLIT2 signalling in the pathogenesis of MDS.
- Feng Xu
- , Ling-Yun Wu
- & Xiao Li
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Article
| Open AccessAF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription
Protein fusions between MLL and AEP (AF4 family/ENL family/P-TEFb) constitutively activate their target genes to immortalize hematopoietic progenitors. Here, Okuda et al. show that MLL-AEP binds SL1, a component of the pre-initiation complex of RNA polymerase (RNAP) I, to initiate RNAP II dependent transcription.
- Hiroshi Okuda
- , Akinori Kanai
- & Akihiko Yokoyama
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Article
| Open AccessmiR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth
The synergism between c-MYC and miR-17-19b plays an important role in lymphoma initiation. In this study, the authors identify a panel of targets co-regulated by miR-17-19b and in MYC-driven lymphoma and unravel the molecular mechanism through which miR-17-19b inhibits MYCtranslation.
- Marija Mihailovich
- , Michael Bremang
- & Tiziana Bonaldi
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Article |
Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth
NF-κB has largely been known as a transcriptional activator. Here the authors show that a transcriptionally repressive NF-κB complex, HDAC4–RelB–p52, maintains repressive chromatin at proapoptotic genes Bim and BMF, and regulates multiple myeloma survival and growth in an ERK1 dependent manner.
- Subrahmanya D. Vallabhapurapu
- , Sunil K. Noothi
- & Sivakumar Vallabhapurapu
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Article
| Open AccessA PI3K p110β–Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis
The tumor suppressor PTEN antagonizes the PI3K signalling pathway and is frequently inactivated in haematological malignancies. Here, the authors unravel the main contribution of the PI3K isoform p110ß to leukemic transformation driven by PTEN-loss.
- Haluk Yuzugullu
- , Lukas Baitsch
- & Jean J. Zhao
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Article
| Open AccessAn LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis
Leukaemic stem cells are prevalent in acute myeloid leukemia. Here, Jung and colleagues derive a signature of 71 methylated genes that characterise these stem cells and find multiple HOXAgenes within the signature.
- Namyoung Jung
- , Bo Dai
- & Andrew P. Feinberg
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Article
| Open AccessGenomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK–STAT pathway in Sézary syndrome
Sézary syndrome is a T cell malignancy that has been poorly characterized at the genome level. In this study, Kielet al. perform whole-genome analyses and identify mutations in the JAK–STAT pathway and show that primary cells are sensitive to JAK inhibitors.
- Mark J. Kiel
- , Anagh A. Sahasrabuddhe
- & Kojo S. J. Elenitoba-Johnson
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Article
| Open AccessAcute DNA damage activates the tumour suppressor p53 to promote radiation-induced lymphoma
p53 can be activated by oncogenic stress to suppress tumourigenesis, but its role in radiation carcinogenesis has not been studied in p53 wild-type mice. Here, Lee et al. show that knocking down p53 during total-body irradiation not only reduces acute toxicity, but prevents the formation of radiation-induced lymphoma.
- Chang-Lung Lee
- , Katherine D. Castle
- & David G. Kirsch
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Article
| Open AccessHigh-resolution analysis of the human T-cell receptor repertoire
Immune system diversity is generated by V(D)J recombination, leading to clonal T-cell lineages. Here the authors investigate the events leading to T-cell diversity through the use of a modified PCR technique combined with deep sequencing.
- Eliana Ruggiero
- , Jan P. Nicolay
- & Christof von Kalle
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Article
| Open AccessDipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells
Chronic myelogenous leukaemia contains a stem cell fraction and targeting this population of cells is an attractive therapeutic strategy. Here, the authors demonstrate that the stem cells take up dipeptides and that inhibiting the dipeptide transporter could reduce the number of these stem cells in mice.
- Kazuhito Naka
- , Yoshie Jomen
- & Seong-Jin Kim
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Article
| Open AccessMEF2B mutations in non-Hodgkin lymphoma dysregulate cell migration by decreasing MEF2B target gene activation
Mutations in the transcription factor MEF2B are found in diffuse large B-cell lymphoma. In this study, the authors map the DNA-binding sites of the transcription factor in cells in vitroand find that the mutations decrease the ability of MEF2B to activate transcription.
- Julia R. Pon
- , Jackson Wong
- & Marco A. Marra
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Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients
Multiple myeloma is an incurable blood cancer with family history being a strong contributing risk factor. Here Ziv et al.perform a genome-wide association study for genetic variation associated with myeloma survival, identifying FOPNL variants associated with worse clinical outcomes.
- Elad Ziv
- , Eric Dean
- & Celine Vachon
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Article
| Open AccessD2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2
IDH1- and IDH2-mutant cancer cells aberrantly accumulate D2-hydroxyglutarate (D2-HG). Here, Lin et al. find loss-of-function mutations in D2-hydroxyglutarate dehydrogenase (D2HGDH), which converts D2-HG to alpha-ketoglutarate (α-KG), in diffuse large B-cell lymphomas and show that D2HGDH via α-KG regulates the expression and activity of IDH2.
- An-Ping Lin
- , Saman Abbas
- & Ricardo C. T. Aguiar
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Article |
A drug-specific nanocarrier design for efficient anticancer therapy
Telodendrimers are versatile and robust nanoparticle-based drug carriers. From a screen of potential small-molecule building blocks, Shi et al.identify rhein-containing telodendrimers as stable and effective nanocarriers of doxorubicin for treating a xenograft Raji lymphoma model.
- Changying Shi
- , Dandan Guo
- & Juntao Luo
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Article
| Open AccessInherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children
Genome-wide association studies indicate a strong genetic susceptibility to acute lymphoblastic leukaemia in children, though the effect on protein-coding genes is not fully understood. Here Xu and Zhang et al. identify a missense variant in CDKN2Awhich reduces tumour suppression.
- Heng Xu
- , Hui Zhang
- & Jun J. Yang
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Article
| Open AccessDevelopmental-stage-dependent transcriptional response to leukaemic oncogene expression
Acute myeloid leukaemia often originates from a chromosomal translocation creating a RUNX1/ETO fusion protein. Here Regha et al, generate a mouse stem cell model and demonstrate the fusion protein disrupts transcription in a differentiation-stage-specific manner.
- Kakkad Regha
- , Salam A. Assi
- & Constanze Bonifer