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Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling
The potential use of circulating tumour DNA in classic Hodgkin lymphoma detection, classification and monitoring is defined.
- Stefan K. Alig
- , Mohammad Shahrokh Esfahani
- & Ash A. Alizadeh
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Article
| Open AccessEpitope editing enables targeted immunotherapy of acute myeloid leukaemia
Epitope engineering of donor haematopoietic stem/progenitor cells endows haematopoietic lineages with selective resistance to CAR T cells or monoclonal antibodies, without affecting protein function or regulation, enabling the targeting of genes that are essential for leukaemia survival and reducing the risk of tumour immune escape.
- Gabriele Casirati
- , Andrea Cosentino
- & Pietro Genovese
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Rewiring cancer drivers to activate apoptosis
A new class of molecules can recruit downstream transcription factors or endogenous cancer drivers to cell death promoters and activate the expression of these genes.
- Sai Gourisankar
- , Andrey Krokhotin
- & Gerald R. Crabtree
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| Open AccessUltraviolet radiation shapes dendritic cell leukaemia transformation in the skin
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) arises from clonal (premalignant) haematopoietic precursors in the bone marrow, and BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet radiation.
- Gabriel K. Griffin
- , Christopher A. G. Booth
- & Andrew A. Lane
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| Open AccessThe menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia
Revumenib, a potent and selective oral inhibitor of the menin–KMT2A interaction, is associated with a low frequency of treatment-related adverse events and promising clinical activity in patients with relapsed or refractory acute leukaemia.
- Ghayas C. Issa
- , Ibrahim Aldoss
- & Eytan M. Stein
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Subtype-specific 3D genome alteration in acute myeloid leukaemia
Extensive genomic analyses of the chromatin architecture in acute myeloid leukaemia reveals several characteristics, including subtype-specific distal enhancers and silencers, that may represent new anticancer therapeutic targets.
- Jie Xu
- , Fan Song
- & Feng Yue
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Article
| Open AccessNon-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL
Non-viral CAR-T cells with gene-specific targeted integration are safe and effective in patients with lymphoma.
- Jiqin Zhang
- , Yongxian Hu
- & He Huang
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Article
| Open AccessThe longitudinal dynamics and natural history of clonal haematopoiesis
A long-term study of 385 human donors reports that driver gene mutations and age determine the lifelong dynamics of clonal haematopoiesis
- Margarete A. Fabre
- , José Guilherme de Almeida
- & George S. Vassiliou
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Life histories of myeloproliferative neoplasms inferred from phylogenies
Whole-genome sequencing of 1,013 clonal haematopoietic colonies from myeloproliferative neoplasms of 12 individuals reveals haematopoietic phylogenies and indicates that driver mutations are acquired sequentially, starting early in life.
- Nicholas Williams
- , Joe Lee
- & Jyoti Nangalia
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Non-genetic determinants of malignant clonal fitness at single-cell resolution
Non-genetic malignant clonal dominance is a cell-intrinsic and heritable property that underpins clonal output and response to therapy in cancer.
- Katie A. Fennell
- , Dane Vassiliadis
- & Mark A. Dawson
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Phase separation drives aberrant chromatin looping and cancer development
The NUP98–HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping.
- Jeong Hyun Ahn
- , Eric S. Davis
- & Gang Greg Wang
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Article |
Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia
Treatment with a specific inhibitor of the N6-methyladenosine methyltransferase METTL3 leads to reduced growth of cancer cells, indicating the potential of approaches targeting RNA-modifying enzymes for anticancer therapy.
- Eliza Yankova
- , Wesley Blackaby
- & Tony Kouzarides
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Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms
Inhibition of YBX1, a downstream target of the Janus kinase JAK2, sensitizes myeloproliferative neoplasm cells to JAK and could provide a means to eradicate such cells in human haematopoietic cancers.
- Ashok Kumar Jayavelu
- , Tina M. Schnöder
- & Florian H. Heidel
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Small-molecule-induced polymerization triggers degradation of BCL6
Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.
- Mikołaj Słabicki
- , Hojong Yoon
- & Benjamin L. Ebert
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IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
IFITM3 shifts upon phosphorylation from acting as an antiviral effector to being a scaffold for PIP3 and thereby amplifies PI3K signalling, which can be co-opted for malignant transformation in B cell leukaemia and lymphoma.
- Jaewoong Lee
- , Mark E. Robinson
- & Markus Müschen
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Single-cell mutation analysis of clonal evolution in myeloid malignancies
The evolution of myeloid malignancies is investigated using combined single-cell sequencing and immunophenotypic analysis.
- Linde A. Miles
- , Robert L. Bowman
- & Ross L. Levine
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Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells
A genome-wide association study identifies 17 genetic loci that are associated with the risk of myeloproliferative neoplasms (MPNs), and shows that the modulation of haematopoietic stem cell function drives MPN risk.
- Erik L. Bao
- , Satish K. Nandakumar
- & Vijay G. Sankaran
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Inherited causes of clonal haematopoiesis in 97,691 whole genomes
Analysis of 97,691 high-coverage human blood DNA-derived whole-genome sequences enabled simultaneous identification of germline and somatic mutations that predispose individuals to clonal expansion of haematopoietic stem cells, indicating that both inherited and acquired mutations are linked to age-related cancers and coronary heart disease.
- Alexander G. Bick
- , Joshua S. Weinstock
- & Pradeep Natarajan
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Signalling input from divergent pathways subverts B cell transformation
Analysis of B-cell leukaemia samples reveals that oncogenic mutations do not cause malignant transformation unless they converge on the same signalling pathway, and that it may be possible clinically to combine inhibition of the principal oncogenic driver with reactivation of divergent pathways.
- Lai N. Chan
- , Mark A. Murakami
- & Markus Müschen
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HBO1 is required for the maintenance of leukaemia stem cells
The MYST acetyltransferase HBO1 is a critical regulator in maintaining leukaemia stem cells, and a small-molecule inhibitor of HBO1 is developed that shows efficacy against a range of acute myeloid leukaemia cells.
- Laura MacPherson
- , Juliana Anokye
- & Mark A. Dawson
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The U1 spliceosomal RNA is recurrently mutated in multiple cancers
A highly recurrent A>C somatic mutation in U1 small nuclear RNA, which alters the splicing pattern of genes that include known drivers of cancer, is identified in several types of tumour.
- Shimin Shuai
- , Hiromichi Suzuki
- & Lincoln D. Stein
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Letter |
Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing.
- Akihide Yoshimi
- , Kuan-Ting Lin
- & Omar Abdel-Wahab
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Letter |
Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion
Leukaemic stem cells in acute myeloid leukaemia are defined by a lack of expression of NKG2D ligands, which mediates their ability to evade surveillance by NK cells.
- Anna M. Paczulla
- , Kathrin Rothfelder
- & Claudia Lengerke
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Somatic mutations and cell identity linked by Genotyping of Transcriptomes
Profiling of over 38,000 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms, using the ‘Genotyping of Transcriptomes’ procedure, reveals that the transcriptional output of these mutations depends upon native cell identity.
- Anna S. Nam
- , Kyu-Tae Kim
- & Dan A. Landau
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Growth dynamics in naturally progressing chronic lymphocytic leukaemia
Analysis of growth dynamics in a dataset from 107 patients with chronic lymphocytic leukaemia (CLL) reveals both exponential and logistic patterns of growth, which are associated with differences in genetic attributes and clinical outcomes.
- Michaela Gruber
- , Ivana Bozic
- & Catherine J. Wu
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Letter |
Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia
A single-cell approach is used to follow the heritable stochastic changes to DNA methylation that occur in primary chronic lymphocytic leukaemia and healthy B cells, allowing the tracing of cell lineage histories and evolution during treatment with ibrutinib.
- Federico Gaiti
- , Ronan Chaligne
- & Dan A. Landau
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Letter |
HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation
An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.
- Ravindra K. Gupta
- , Sultan Abdul-Jawad
- & Eduardo Olavarria
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Functional genomic landscape of acute myeloid leukaemia
Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.
- Jeffrey W. Tyner
- , Cristina E. Tognon
- & Brian J. Druker
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The genetic basis and cell of origin of mixed phenotype acute leukaemia
A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia.
- Thomas B. Alexander
- , Zhaohui Gu
- & Charles G. Mullighan
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Letter |
Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia
The inactivation of tumour suppressor genes at the level of mRNA occurs by the generation of truncated proteins in leukaemia.
- Shih-Han Lee
- , Irtisha Singh
- & Christine Mayr
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Leukaemia hijacks a neural mechanism to invade the central nervous system
Expression of α6 integrin enables acute lymphoblastic leukaemia cells to use neural migratory pathways to invade the central nervous system and metastasize to the brain.
- Hisayuki Yao
- , Trevor T. Price
- & Dorothy A. Sipkins
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Letter |
Histidine catabolism is a major determinant of methotrexate sensitivity
Histidine metabolism influences the sensitivity of cancer cells to methotrexate, with mice bearing leukaemia xenografts showing increased response to the drug upon histidine supplementation.
- Naama Kanarek
- , Heather R. Keys
- & David M. Sabatini
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Letter |
Prediction of acute myeloid leukaemia risk in healthy individuals
Individuals who are at high risk of developing acute myeloid leukaemia can be identified years before diagnosis using genetic information from blood samples.
- Sagi Abelson
- , Grace Collord
- & Liran I. Shlush
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Letter |
Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations
A new mechanism of acquired clinical resistance in two patients with acute myeloid leukaemia driven by mutant IDH2 is described, in which a second-site mutation on the wild-type allele induces therapeutic resistance to IDH2 inhibitors.
- Andrew M. Intlekofer
- , Alan H. Shih
- & Eytan M. Stein
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Letter |
A multiprotein supercomplex controlling oncogenic signalling in lymphoma
A pro-survival multiprotein signalling supercomplex consisting of the B cell receptor, MYD88, TLR9 and mTOR is discovered that coordinates NF-κB activation in diffuse large B cell lymphoma, and provides mechanistic insight into the efficacy of drug combinations.
- James D. Phelan
- , Ryan M. Young
- & Louis M. Staudt
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Letter |
Structural basis for DNMT3A-mediated de novo DNA methylation
A crystal structure of DNMT3A and its regulatory partner DNMT3L bound to DNA reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.
- Zhi-Min Zhang
- , Rui Lu
- & Jikui Song
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Letter |
Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia
Mutations in the nucleotidase-encoding gene NT5C2 drive chemotherapy resistance in relapsed acute lymphoid leukaemia but the mutations also lead to a loss-of-fitness phenotype and to collateral drug sensitivity, which could be exploited for therapy.
- Gannie Tzoneva
- , Chelsea L. Dieck
- & Adolfo A. Ferrando
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Letter |
Senescence-associated reprogramming promotes cancer stemness
Cellular senescence induced by chemotherapy leads to the acquisition of stemness in cancer cells, which results in enhanced tumour-promoting capacity after forced release or spontaneous escape from the senescent cell-cycle arrest.
- Maja Milanovic
- , Dorothy N. Y. Fan
- & Clemens A. Schmitt
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Letter |
Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control
The methyltransferase METTL3 promotes the leukaemic state in acute myeloid leukaemia (AML) by catalysing the m6A RNA modification through its recruitment on the transcription start sites of AML-associated genes.
- Isaia Barbieri
- , Konstantinos Tzelepis
- & Tony Kouzarides
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Letter |
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
The mechanistic basis for the role of the metabolic enzyme BCAA transaminase 1 (BCAT1) in acute myeloid leukaemias.
- Simon Raffel
- , Mattia Falcone
- & Andreas Trumpp
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Article |
Ascorbate regulates haematopoietic stem cell function and leukaemogenesis
Ascorbate depletion in mice increased haematopoietic stem-cell frequency and promoted leukaemogenesis, partly by reducing the function of the Tet2 tumour suppressor enzyme.
- Michalis Agathocleous
- , Corbin E. Meacham
- & Sean J. Morrison
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Letter |
Tracing the origins of relapse in acute myeloid leukaemia to stem cells
Identification of the cell types from which relapse arises in acute myeloid leukaemia, by following leukaemia propagation from patient-derived leukaemia samples.
- Liran I. Shlush
- , Amanda Mitchell
- & John E. Dick
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Letter |
The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition
Combined studies in MYC-driven mouse lymphomas and human Burkitt lymphoma unravel an essential role for the B-cell antigen receptor in the control of tumour B-cell fitness both in vitro and in vivo, with possible biological and clinical implications.
- Gabriele Varano
- , Simon Raffel
- & Stefano Casola
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Letter |
Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for disease progression in chronic myeloid leukaemia.
- Ayuna Hattori
- , Makoto Tsunoda
- & Takahiro Ito
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Article |
Myeloid progenitor cluster formation drives emergency and leukaemic myelopoiesis
During emergency myelopoiesis in mice, clusters of self-renewing granulocyte/macrophage progenitors (GMP) are transiently formed in the bone marrow cavity to produce a burst of myeloid cells; in leukaemia, GMP clusters persist and constantly generate myeloid leukaemia cells.
- Aurélie Hérault
- , Mikhail Binnewies
- & Emmanuelle Passegué
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Letter |
The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1
The selective allosteric ABL1 inhibitor ABL001 (asciminib) represents a new inhibitory mechanism for BCR–ABL1-driven malignancies, and its efficacy and evolving mechanisms of resistance do not overlap with those of other BCR–ABL1 kinase inhibitors.
- Andrew A. Wylie
- , Joseph Schoepfer
- & William R. Sellers
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Letter |
Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens
Evidence for the abundant presentation of class II neoantigens by a human B-cell lymphoma.
- Michael S. Khodadoust
- , Niclas Olsson
- & Ash A. Alizadeh
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Letter |
Transcription control by the ENL YEATS domain in acute leukaemia
ENL, identified in a genome-scale loss-of-function screen as a crucial requirement for proliferation of acute leukaemia, is required for leukaemic gene expression, and its YEATS chromatin-reader domain is essential for leukaemic growth.
- Michael A. Erb
- , Thomas G. Scott
- & James E. Bradner
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Letter |
ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia
The chromatin-reader protein ENL regulates oncogenic programs in acute myeloid leukaemia by binding via its YEATS domain to acetylated histones on the promoters of actively transcribed genes and recruiting the transcriptional machinery.
- Liling Wan
- , Hong Wen
- & Xiaobing Shi