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| Open AccessGenome-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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Article
| Open AccessTargeting 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 AccessTET2 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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Article
| Open AccessInhibition 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 AccessSingle 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 AccessThe 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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Article
| Open AccessIn vivo inducible reverse genetics in patients’ tumors to identify individual therapeutic targets
Preclinical molecular models are useful that mimic a patient´s response to targeted therapy. Here, the authors establish an in vivo inducible RNAi-mediated gene silencing system in patient-derived xenograft models of acute leukemia to identify individual vulnerabilities and therapeutic targets.
- Michela Carlet
- , Kerstin Völse
- & Irmela Jeremias
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Article
| Open AccessAdipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence
How the bone marrow microenvironment evolves during induction chemotherapy to facilitate acute lymphoblastic leukaemia (ALL) survival remains unclear. Here the authors show that adipocytes emergent during ALL therapy aid the survival of ALL cells through a restrictive effect on the ALL proteome.
- Q. Heydt
- , C. Xintaropoulou
- & B. Patel
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Article
| Open AccessThe 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 AccessMulti-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
Chronic lymphocytic leukemia has been studied using multiple levels of omics data. Here, the authors use exome sequencing, SNP, protein and gene expression data to identify distinct biologic tumor subtypes with heterogeneous prognostic impact after chemo- or immunochemotherapy.
- Johannes Bloehdorn
- , Andrejs Braun
- & Daniel Mertens
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Article
| Open AccessInteracting evolutionary pressures drive mutation dynamics and health outcomes in aging blood
Age-related clonal hematopoiesis is associated with risk for diseases like acute myeloid leukemia (AML), yet it is unclear why some individuals do not progress despite having AML driver mutations. Here, the authors use deep learning and population genetics models to investigate how the interplay of positive and negative selection influences AML progression.
- Kimberly Skead
- , Armande Ang Houle
- & Philip Awadalla
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Article
| Open AccessHuman 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
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Article
| Open AccessThe evolution of hematopoietic cells under cancer therapy
The mutational effects of chemotherapies on healthy cells are unclear. Here, the authors show that the mutational signature of platinum-based drugs -but not 5-fluorouracil- is detectable in secondary acute myeloid leukemia, implying that the clonal expansion begins after the start of therapy.
- Oriol Pich
- , Albert Cortes-Bullich
- & Nuria Lopez-Bigas
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Article
| Open AccessFunctional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome
Germline mutations in the DNMT3A gene can cause an overgrowth syndrome associated with behavioural and hematopoietic phenotypes. Here the authors describe a mouse model of this syndrome that recapitulates many of these features, including conserved alterations in DNA methylation in the blood cells of both species.
- Amanda M. Smith
- , Taylor A. LaValle
- & Timothy J. Ley
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Article
| Open AccessOncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.
- Quentin Van Thillo
- , Jolien De Bie
- & Charles E. de Bock
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Article
| Open Access3D genome alterations associated with dysregulated HOXA13 expression in high-risk T-lineage acute lymphoblastic leukemia
The non-coding genome of T-ALL has not been extensively studied. Here, the authors conduct RNA-seq, ATAC-seq and Hi-C seq analyses and find that T-ALL associated neo-loops may regulate key transcription factors including HOXA13; the aberrant expression of which is associated with poor prognosis.
- Lu Yang
- , Fengling Chen
- & Hong Wu
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Article
| Open AccessTargeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia
Current therapeutic approaches in chronic lymphocytic leukemia (CLL) focus on the suppression of PI3K/AKT signaling. Here, the authors show that CLL cells are vulnerable to hyperactivation of the PI3K/AKT signaling pathway and suggest this as a promising concept for CLL therapy.
- Veronika Ecker
- , Martina Stumpf
- & Maike Buchner
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Article
| Open AccessQuantitative single-cell proteomics as a tool to characterize cellular hierarchies
Single-cell proteomics can provide insights into the molecular basis for cellular heterogeneity. Here, the authors develop a multiplexed single-cell proteomics and computational workflow, and show that their strategy captures the cellular hierarchies in an Acute Myeloid Leukemia culture model.
- Erwin M. Schoof
- , Benjamin Furtwängler
- & Bo T. Porse
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Article
| Open AccessGut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients
The combination of chemotherapy and broad-spectrum antibiotics induces gut microbiota (GM) dysbiosis in acute myeloid leukaemia (AML) leading to additional complications. Here, the authors report the efficacy in GM restoration and safety of autologous faecal microbiota transfer in treated AML patients in a phase II clinical trial.
- Florent Malard
- , Anne Vekhoff
- & Mohamad Mohty
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Article
| Open AccessRAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis
Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.
- Ryan M. Carr
- , Denis Vorobyev
- & Mrinal M. Patnaik
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Article
| Open AccessLeukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia
The regulation of resistance to IDH inhibitors in acute myeloid leukaemia is not completely understood. Here the authors reveal with integrative multi-omics analyses that stemness features are major drivers of primary resistance, while high-risk mutations drive acquired resistance.
- Feng Wang
- , Kiyomi Morita
- & Koichi Takahashi
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Article
| Open AccessProteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures
NOTCH1 is a driver of T-cell acute lymphoblastic leukemia that can be inhibited by γ-secretase inhibitors (GSIs), but their clinical efficacy is limited. Here, the authors compare the phosphoproteomes of GSI resistant and sensitive models, and identify potential kinase targets to overcome GSI resistance.
- Giulia Franciosa
- , Jos G. A. Smits
- & Jesper V. Olsen
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Article
| Open AccessA clinical transcriptome approach to patient stratification and therapy selection in acute myeloid leukemia
Several genomic features have been found for acute myeloid leukaemia (AML) but targeted clinical genetic testing fails to predict prognosis. Here, the authors generate an AML prognostic score from RNA-seq data of patients, which successfully stratifies AML patients and which may provide guidance for therapeutic strategies.
- T. Roderick Docking
- , Jeremy D. K. Parker
- & Aly Karsan
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Article
| Open AccessCut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia
Cut-like homeobox 1 (CUX1) is a haploinsufficient tumor suppressor commonly inactivated in acute myeloid leukemia and high-risk myelodysplasia. Here, in a genetically modified murine model, the authors show that CUX1 deficiency impairs apoptosis leading to leukemia when combined with mutant Flt3-ITD.
- Emmanuelle Supper
- , Saskia Rudat
- & Chi C. Wong
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Article
| Open AccessRecurrent deletions in clonal hematopoiesis are driven by microhomology-mediated end joining
The mutational mechanisms that produce insertions and deletions that lead to clonal hematopoiesis are poorly understood. Here the authors show evidence that frequent deletions that are relevant to myeloid malignancies could be produced by PARP1-dependent microhomology-mediated end joining.
- Tzah Feldman
- , Akhiad Bercovich
- & Liran I. Shlush
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Article
| Open AccessHOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia
Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.
- Ganqian Zhu
- , Huacheng Luo
- & Mingjiang Xu
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Article
| Open AccessJoint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia
It is currently difficult to map DNA variants and surface phenotypes in the same cells, preventing direct linkage of phenotype and genotype. Here the authors report DAb-seq for simultaneous capture of DNA genotype and cell surface phenotype from single cells at high throughput.
- Benjamin Demaree
- , Cyrille L. Delley
- & Adam R. Abate
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Article
| Open AccessIdentification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics
Leukaemic stem cells drive acute myeloid leukaemia (AML) progression and relapse but they are incompletely characterized. Here, the authors combine single-cell transcriptomics and clonal tracking using nuclear and mitochondrial somatic variants to distinguish healthy, pre-leukaemic and leukaemic stem cells in AML.
- Lars Velten
- , Benjamin A. Story
- & Lars M. Steinmetz
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Article
| Open AccessBiological and therapeutic implications of a unique subtype of NPM1 mutated AML
Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.
- Arvind Singh Mer
- , Emily M. Heath
- & Benjamin Haibe-Kains
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Article
| Open AccessZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism
The fusion gene ZMYND11-MBTD1 (ZM) is present in a subgroup of patients with acute myeloid leukaemia (AML). Here, the authors show that ZM expression induces AML in a murine model though activating the NuA4/TIP60 histone acetyltransferase complex.
- Jie Li
- , Phillip M. Galbo Jr.
- & Gang Greg Wang
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Article
| Open AccessThe acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms
Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.
- Jason R. Schwartz
- , Jing Ma
- & Jeffery M. Klco
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Article
| Open AccessSingle-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy
CD19-negative relapses are observed in patients with B-cell acute lymphoblastic leukemia (B-ALL) treated with anti-CD19 CAR-T cells. Here, by single-cell RNA sequencing of leukemic cells in a patient with B-ALL, the authors show that pre-existing CD19 negative leukemic subclones are present before CAR-T cell therapy and can account for the relapse.
- Tracy Rabilloud
- , Delphine Potier
- & Dominique Payet-Bornet
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Article
| Open AccessDirect control of CAR T cells through small molecule-regulated antibodies
Many next-generation antibody therapeutics have enhanced potency but the risk of adverse events. Here the authors develop a conditionally activated, single-module CAR.
- Spencer Park
- , Edward Pascua
- & Javier Chaparro-Riggers
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Article
| Open AccessGenome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia
The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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Article
| Open AccessRUNX1/RUNX1T1 mediates alternative splicing and reorganises the transcriptional landscape in leukemia
The fusion gene RUNX1/RUNX1T1 is oncogenic in acute myeloid leukemia. Here, the authors show that the fusion gene alters the transcriptional landscape of the cells by changing the structure of the 5’UTR, altering isoform expression, and controlling the expression of splicing factors.
- Vasily V. Grinev
- , Farnaz Barneh
- & Olaf Heidenreich
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Article
| Open AccessBRD4-mediated repression of p53 is a target for combination therapy in AML
MDM2 and BET inhibitors have shown efficacy in AML treatment. Here, the authors show that the two compounds can synergize through both p53 protein stabilization and inhibition of BRD4-mediated repression of p53 target genes.
- Anne-Louise Latif
- , Ashley Newcombe
- & Peter D. Adams
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Article
| Open AccessImaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML
The role of mTORC1 in AML has not yet been proven due to the mixed results of its inhibitors in clinical trials. Here the authors show the real-time dynamics of the mTORC1 pathway in association with AML growth and response to chemotherapy with fluorescent markers, providing guidance for timed intervention with pathway-specific inhibitors.
- Toshihiko Oki
- , Francois Mercier
- & David T. Scadden
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Article
| Open AccessTargeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.
- Hu Lei
- , Han-Zhang Xu
- & Ying-Li Wu
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Article
| Open AccessSmall molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells
The tumour microenvironment provides signals to support leukaemic stem cells (LSC) maintenance and chemoresistance. Here, the authors show that disrupting niche-associated signalling by inhibiting receptor-mediated endocytosis with a dynamin GTPase inhibitor overcomes chemoresistance of LSC.
- Cedric S. Tremblay
- , Sung Kai Chiu
- & David J. Curtis
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Article
| Open AccessA stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia
Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells.
- Kyle Spinler
- , Jeevisha Bajaj
- & Tannishtha Reya
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Article
| Open AccessInfluence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia
CAR T therapy has some efficacy in the treatment of patients with refractory/relapsed B-cell acute lymphoblastic leukemia; however in some patients further relapse is encountered. Here, the authors conduct a Phase II clinical trial of a CD19 CAR T and demonstrate that patients with extramedullary disease are more likely to relapse than those without.
- Furun An
- , Huiping Wang
- & Zhimin Zhai
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Article
| Open AccessEnhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9
Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells.
- Lintao Liu
- , Enguang Bi
- & Qing Yi
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Article
| Open AccessClonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.
- Kiyomi Morita
- , Feng Wang
- & Koichi Takahashi
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Article
| Open AccessT cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect
In hematopoietic stem cell transplants, T cells mediate graft-versus-leukemia (GVL), but GVL can fail leading to leukemia relapse. Here the authors use a mouse model in which T cells target the minor histocompatibility antigen H60 to show how this can occur, characterize the CD8+ T cell response and demonstrate how anti-CD40 antibody therapy improves GVL.
- Meng Zhou
- , Faruk Sacirbegovic
- & Warren D. Shlomchik
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Article
| Open AccessChlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V
Receptor tyrosine kinase mutations are frequent and associated with poor prognosis in acute myeloid leukemia (AML). Here the authors show that the antipsychotic drug chlorpromazine reduces AML cells viability by perturbing the intracellular localization of FLT3-ITD and KIT-D816V.
- Shinya Rai
- , Hirokazu Tanaka
- & Itaru Matsumura
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Article
| Open AccessAutophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites
How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML.
- Claudie Bosc
- , Nicolas Broin
- & Carine Joffre
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Article
| Open AccessEndogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia
Transposable elements are a potential source of transcriptional regulators, but how these sequences contribute to oncogenesis remains poorly understood. Here, the authors identify endogenous retroviruses (ERVs) with acute myeloid leukemia (AML)-associated enhancer chromatin signatures, and provide evidence that ERV activation provides an additional layer of gene regulation in AML.
- Özgen Deniz
- , Mamataz Ahmed
- & Miguel R. Branco
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Article
| Open AccessMechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation.
- Yi Zhang
- , Yiran Guo
- & Tatiana G. Kutateladze
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Article
| Open AccessHematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells in the majority of patients with leukemia but not during normal blood formation. Here, the authors report a mouse model with conditional Cdx2 expression showing de novo leukemic transformation, and use it to optimize treatment in high-risk AML.
- Therese Vu
- , Jasmin Straube
- & Steven W. Lane