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Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies
IFNγ signaling is important in the pathogenesis and immune response, emphasizing the need for investigation of its role. Here, the authors show that IFNγ plays a key role in shaping immune microenvironment in AML and developing resistance, providing insights for potential therapeutic strategies.
- Bofei Wang
- , Patrick K. Reville
- & Hussein A. Abbas
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Article
| Open Access
Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting
PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.
- Yasuo Kubota
- , Xiaorong Gu
- & Jaroslaw P. Maciejewski
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Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia
The cellular hierarchies in acute promyelocytic leukemia (APL) remain to be explored. Here, the authors perform single-cell RNA sequencing of 16 APL patients to characterise its cellular composition and develop an APL-specific stemness score for assessing the risk of early death in APL.
- Wen Jin
- , Yuting Dai
- & Kankan Wang
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| Open Access
Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth
In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.
- Sophie G. Kellaway
- , Sandeep Potluri
- & Constanze Bonifer
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| Open Access
TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells
The immune receptor Transmembrane and immunoglobulin domain containing 2 (TMIGD2) mediates T-cell and nature killer cells co-stimulation upon B7-family HHLA2 engagement. Here, the authors show that TMIGD2 is expressed in Acute Myeloid Leukaemia stem cells regulating self-renewal and differentiation to facilitate leukemogenesis.
- Hao Wang
- , R. Alejandro Sica
- & Xingxing Zang
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| Open Access
Integrative genotyping of cancer and immune phenotypes by long-read sequencing
Single-cell transcriptomics excel in cell subset classification and can be augmented by suitable genotype information. Here the authors devise a long-read sequencing workflow, termed nanoranger, for detection of molecular barcodes from single-cell cDNA and apply this to clonal tracking of acute myeloid leukemia and identification of complex immune phenotypes.
- Livius Penter
- , Mehdi Borji
- & Catherine J. Wu
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| Open Access
Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens
The role of HOXA9 in binding to noncoding regulatory sequences and regulates the downstream genes in MLL gene rearrangements (MLL-r) leukemia. Here, the use of CRISPR-mediated loss-of-function screen against HOXA9-bound peaks and integrative approaches reveal the noncoding regulation mechanism of HOXA9.
- Shaela Wright
- , Xujie Zhao
- & Chunliang Li
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Article
| Open Access
Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open Access
Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia
Single-cell RNA-seq could help identify acute myeloid leukaemia (AML) patients at high risk of relapse after therapy. Here, the authors use single-cell RNA-seq from paediatric AML samples to construct a 7-gene signature that can identify malignant cells at diagnosis, which are distinctly associated with relapse or complete remission.
- Hope Mumme
- , Beena E. Thomas
- & Manoj Bhasin
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Article
| Open Access
TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression
TET2 and GATA2 are two frequently co-mutated genes in CEBPA double mutated acute myeloid leukemia (AML). Here the authors show that the underlying mechanism for this cooccurrence is for TET2 loss-of-function mutation to counteract the increase in GATA2 expression, which is disadvantageous to these type of AML cells.
- Elizabeth Heyes
- , Anna S. Wilhelmson
- & Bo T. Porse
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Article
| Open Access
The NCOR-HDAC3 co-repressive complex modulates the leukemogenic potential of the transcription factor ERG
ETS transcription factor ERG has been implicated in numerous cancers, including leukemia. Here, the authors show that ERG interaction with the NCoR-HDAC3 co-repressor complex is essential for its leukemogenic activity. Highlighting this interaction as a potential therapeutic target, HDAC3 inhibition led to reduced growth of ERG-dependent leukemia cells in vitro and in vivo.
- Eitan Kugler
- , Shreyas Madiwale
- & Shai Izraeli
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| Open Access
ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia
BCL-2 inhibition using Venetoclax has emerged as a promising therapy in Acute Myeloid Leukaemia (AML), but primary and acquired resistance is a main limitation of this treatment. Here, the authors show that the ABC transporter ABCC1 (MRP1) together with glutathione, are associated with Venetoclax resistance and represent potential targets to sensitize AML cells to BCL-2 inhibition.
- Jessica Ebner
- , Johannes Schmoellerl
- & Florian Grebien
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COMPASS: joint copy number and mutation phylogeny reconstruction from amplicon single-cell sequencing data
Understanding the evolution of a tumor is important for predicting its resistance to treatment. This paper presents a new computational method, COMPASS, for inferring the joint phylogeny of single nucleotide variants and copy number alterations from targeted scDNAseq data.
- Etienne Sollier
- , Jack Kuipers
- & Katharina Jahn
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| Open Access
Molecular patterns identify distinct subclasses of myeloid neoplasia
Myeloid neoplasias can show complex mutation patterns and molecular features. Here, the authors apply machine learning to classify risk groups of myeloid neoplasia which may correlate with differential response to treatment.
- Tariq Kewan
- , Arda Durmaz
- & Jaroslaw P. Maciejewski
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Article
| Open Access
Oncogenic drivers dictate immune control of acute myeloid leukemia
There is increasing evidence of a functional interaction between acute myeloid leukemia (AML) and immune cells, influencing disease outcome. Here the authors study how distinct oncogenes differentially affect the host immune response to leukemic cells in preclinical models of AML.
- Rebecca J. Austin
- , Jasmin Straube
- & Megan J. Bywater
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| Open Access
Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis
Age related accumulation of adipocytes in the bone marrow could alter normal and leukemic haematopoiesis. Here, in fatty bone marrow (FBM) preclinical models, the authors show that inflammatory cytokines increased in the FBM, such as IL-6, promote DNMT3a driven clonal hematopoiesis.
- N. Zioni
- , A. Akhiad Bercovich
- & Liran I. Shlush
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| Open Access
MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins
Altered transcriptional machinery promotes aberrant self-renewal of non-stem hematopoietic progenitors. Here the authors show that AF10 fusion proteins cause aberrant self-renewal via ENL, which promotes leukemic transformation by binding to MOZ/MORF lysine acetyltransferases
- Yosuke Komata
- , Akinori Kanai
- & Akihiko Yokoyama
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| Open Access
Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia
Relapse within acute myeloid leukaemia may be driven by the presence of leukaemia stem cells. Here, the authors use single cell RNA-seq seq to characterise leukemia stem cells, and show miR-126 as a potential marker of resistance.
- Matteo Maria Naldini
- , Gabriele Casirati
- & Bernhard Gentner
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| Open Access
Early response evaluation by single cell signaling profiling in acute myeloid leukemia
The molecular mechanisms underlying response to chemotherapy in Acute myeloid leukemia (AML) remain to be explored. Here, the authors perform 36-dimensional mass cytometry in 32 AML patients during intensive chemotherapy and suggest functional signalling analysis for prognosis prediction early after treatment in AML.
- Benedicte Sjo Tislevoll
- , Monica Hellesøy
- & Bjørn Tore Gjertsen
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| Open Access
Inflammatory bone marrow signaling in pediatric acute myeloid leukemia distinguishes patients with poor outcomes
IL6 expression in the bone marrow is associated with reduced survival in paediatric AML. Here, the authors used RNA-seq to identify treatment resistance-associated co-occurring inflammatory signalling in leukemic cells.
- Hamid Bolouri
- , Rhonda E. Ries
- & Soheil Meshinchi
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Article
| Open Access
RNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4
The establishment of a mouse model of MLL-AF4-induced leukaemia is a challenge as the introduction of fusion gene of human MLL-AF4 does not cause leukaemia in mice. Here the authors reveal that MLL-AF4 is post-transcriptionally regulated by RNA-binding proteins that inhibits MLL-AF4 translation, thus, hampering MLL-AF4-mediated leukemic transformation.
- Hiroshi Okuda
- , Ryo Miyamoto
- & Akihiko Yokoyama
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Article
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MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia
The links between DNA methylation and gene expression are poorly understood on large-scale. Here the authors show that MIR retrotransposons within introns can play this role in acute myeloid leukemia harbouring mutations in epigenetic modifiers.
- Aristeidis G. Telonis
- , Qin Yang
- & Maria E. Figueroa
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Article
| Open Access
HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia
Acute myeloid leukaemia (AML) is maintained by self-renewing leukemic stem cells. Here the authors show that Heat Shock Transcription Factor 1 (HSF1) is specifically required for the maintenance of AML stem cells, while sparing steady-state and stressed haematopoiesis and that pharmacologically targeting HSF1 may have broad anti-leukemic effects.
- Qianze Dong
- , Yan Xiu
- & Chen Zhao
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Article
| Open Access
HOXA9 has the hallmarks of a biological switch with implications in blood cancers
HOXA9 plays an important role in acute myeloid leukaemia (AML), but its relevance for other blood malignancies is unclear. Here, the authors show that HOXA9 has a binary switch function that can clinically stratify AML patients, and model how the interactions with JAK2, TET2 and NOTCH impact myeloproliferative neoplasms.
- Laure Talarmain
- , Matthew A. Clarke
- & Benjamin A. Hall
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Article
| Open Access
Graphdiyne oxide nanosheets display selective anti-leukemia efficacy against DNMT3A-mutant AML cells
DNA methyltransferase 3A, a mutated gene associated with hematologic malignancies in age-related clonal haematopoiesis lacks targeted therapies. Here, the authors screen carbon nanomaterials and find graphdiyne oxide binds to mutant cells and disrupts cellular processes with a therapeutic effect in vitro and in vivo.
- Qiwei Wang
- , Ying Liu
- & Pengxu Qian
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| Open Access
Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
Relapsed pediatric acute myeloid leukemia is associated with poor prognosis. Here, the authors use RNA-seq data from 1503 primary samples to create a combined transcriptional and cytomolecular signature to improve relapse risk prediction.
- Benjamin J. Huang
- , Jenny L. Smith
- & Soheil Meshinchi
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Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors
The development of IDH variant inhibitors is a breakthrough as it is the first time metabolism has been successfully targeted by small molecule drugs in cancer. Here the authors report studies on resistance to the pioneer drug ivosidenib leading to identification of inhibitors retaining activity.
- Raphael Reinbold
- , Ingvild C. Hvinden
- & Christopher J. Schofield
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Article
| Open Access
Unified classification and risk-stratification in Acute Myeloid Leukemia
Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.
- Yanis Tazi
- , Juan E. Arango-Ossa
- & Elli Papaemmanuil
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| Open Access
The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors
Leukemic stem cells (LSCs) drive chemoresistance and relapse in acute myeloid leukemia. Here, the authors show that the splicing factor RBM17 supports LSCs through avoiding nonsense-mediated decay of pro-leukaemic factors such as the translation initiation factor EIF4A2.
- Lina Liu
- , Ana Vujovic
- & Yu Lu
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Article
| Open Access
Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.
- Mahmoud A. Bassal
- , Saumya E. Samaraweera
- & Richard J. D’Andrea
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| Open Access
Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate
The role of gut microbiota in acute myeloid leukaemia (AML) remains unclear. Here, the authors show disordered gut microbiota and reduced butyrate cause intestinal barrier damage in AML mice, with increased plasma LPS that accelerates AML progression.
- Ruiqing Wang
- , Xinyu Yang
- & Daoxin Ma
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| Open Access
Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia
CD123, the interleukin-3 receptor alpha chain, is aberrantly expressed in acute myeloid leukemia blasts and leukemia stem cells. Here the authors report the design and characterize the anti-tumor activity of allogeneic CD123-targeted CAR-T cells as a therapeutic approach for acute myeloid leukemia.
- Mayumi Sugita
- , Roman Galetto
- & Monica L. Guzman
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Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia
Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.
- Rebecca Anderson
- , Lance D. Miller
- & Timothy S. Pardee
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| Open Access
Distinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification
The genomic landscape of pediatric acute myeloid leukemia (AML) has mostly been characterised for Western populations. Here, the authors identify potential driver alterations in Chinese pediatric AML, which differ from Western populations, and propose a prognostic risk classification model.
- Ting Liu
- , Jianan Rao
- & Shuhong Shen
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| Open Access
Comparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells
Clonal dynamics and selection have not been fully understood in patient-derived xenografts (PDX) of acute myeloid leukemia (AML). Here, the authors generate 160 AML-PDX models to track the clonal dynamics of primary and relapsed AML, and find selectively enriched subclones that are associated with resistance to therapy.
- Naomi Kawashima
- , Yuichi Ishikawa
- & Hitoshi Kiyoi
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| Open Access
The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia
Acute myeloid leukemia (AML) is genetically a very heterogeneous disease. Here, Erdem et al. uncover heterogeneity in the metabolic landscape of AML and identify Pyruvate dehydrogenase kinase 1 (PDK1) as a targetable determinant of different metabolic states in distinct subtypes of AML.
- Ayşegül Erdem
- , Silvia Marin
- & Jan Jacob Schuringa
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Article
| Open Access
Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia
Individual studies have been underpowered to draw clear associations between clonal heterogeneity and response to therapy in acute myeloid leukemia (AML). Here, the authors aggregate multiple AML cohorts and are able to correlate the clonal abundance of somatic mutations with clinical outcomes and drug sensitivity.
- Brooks A. Benard
- , Logan B. Leak
- & Ravindra Majeti
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Article
| Open Access
Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy
Differentiation therapy induces the maturation and clearance of acute myeloid leukemia cells. Here, using a mouse model, the authors show that a specific lineage of mature leukemia-derived cells persists during remission and is responsible for disease relapse.
- Steven Ngo
- , Ethan P. Oxley
- & Ross A. Dickins
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Article
| Open Access
Discovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells
CRISPR-based knockout screens in cancer cells have suggested the existence of proliferation suppressor genes (PSG). Here, the authors develop an approach to systematically identify them, and reveal a PSG module involved in fatty acid synthesis and tumour suppression in acute myeloid leukemia cell lines.
- W. Frank Lenoir
- , Micaela Morgado
- & Traver Hart
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Article
| Open Access
Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia
The success of CAR-T cells for treating acute myeloid leukaemia (AML) is hampered by toxicity to normal cells and low CAR-T cell persistence. Here, the authors show that the demethylating compound 5′-Azacitdine increases anti-CD123 CAR-T cell cytotoxicity against AML.
- Nadia El Khawanky
- , Amy Hughes
- & Robert Zeiser
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Article
| Open Access
Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation
Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.
- Yuxuan Liu
- , Zhimin Gu
- & Jian Xu
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Article
| Open Access
Genome-wide association study identifies susceptibility loci for acute myeloid leukemia
Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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| Open Access
Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance
miR-126 is highly expressed in inv(16) Acute myeloid leukemia (AML) but its role is unclear. Here, the authors show that the aberrant expression of miR-126 in inv(16) AML is directly due to the CBFB-MYH11 fusion gene and that it can promote AML development and leukemia stem cell maintenance, highlighting miR-126 as a therapeutic target for inv(16) AML patients
- Lianjun Zhang
- , Le Xuan Truong Nguyen
- & Ya-Huei Kuo
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Article
| Open Access
TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.
- Morten Tulstrup
- , Mette Soerensen
- & Kirsten Grønbæk
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| Open Access
Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
Azacitidine (AZA) treatment is used for patients with myelodysplasias that cannot undergo bone marrow transplantation; however, AZA treatment is only partially effective. Here the authors show synergy of AZA with compounds inhibiting the chromatin regulators CBP and p300, which is mediated by the RNA-dependent functions of AZA affecting protein translation.
- Jeannine Diesch
- , Marguerite-Marie Le Pannérer
- & Marcus Buschbeck
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Article
| Open Access
Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy
The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.
- Hussein A. Abbas
- , Dapeng Hao
- & Andrew Futreal
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Article
| Open Access
The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
Chromosome rearrangements can be a cause of altered oncogene expression in cancer, such as a 3q26 translocation in some acute myeloid leukemias (AML) that leads to overexpression of EVI1. Here the authors engineer this rearrangement in a cell line and show that EVI1 overexpression is a result of ‘enhancer hijacking’ of the MYC superenhancer, which is facilitated by CTCF-mediated loops.
- Sophie Ottema
- , Roger Mulet-Lazaro
- & Ruud Delwel
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| Open Access
The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors
Epigenetic changes are implicated in Acute myeloid leukemia (AML) tumorigenesis. Here, the authors show that the ubiquitin ligase RNF5 and its substrate RBBP4 contribute to AML development by regulating epigenetic-controlled transcription which determines AML sensitivity to HDAC inhibitors.
- Ali Khateb
- , Anagha Deshpande
- & Ze’ev A. Ronai
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Article
| Open Access
Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia
Leukaemia therapy may benefit from the use of antigens that are less restricted to individual donors. Here the authors engineered T cells with a TCR specific for a CD1c restricted lipid leukaemia antigen and show that they can protect against disease progression in mouse leukaemia xenograft models.
- Michela Consonni
- , Claudio Garavaglia
- & Giulia Casorati
Translation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis