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| Open AccessProteogenomics refines the molecular classification of chronic lymphocytic leukemia
Proteomics can be used to refine cancer classification. Here, the authors characterise chronic lymphocytic leukaemia patients by proteogenomics, and identified a subtype of patients with poor prognosis associated with aberrant B cell receptor signalling.
- Sophie A. Herbst
- , Mattias Vesterlund
- & Sascha Dietrich
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Article
| Open AccessHSF1 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 AccessDNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia
The role of DNA methylation in predisposing to pediatric acute lymphoblastic leukemia remains unknown. Here, the authors utilize a discordant twin model to investigate how DNA methylation variation contributes to disease risk in genetically identical subjects.
- Eric M. Nickels
- , Shaobo Li
- & Joseph L. Wiemels
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Article
| Open AccessHOXA9 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 AccessTP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma
Inhibition of the protein arginine methyltransferase PRMT5 has been suggested as a promising therapy for lymphoma. Here, the authors show that TP53 loss of function and MUSASHI-2 (MSI2) expression are biomarkers of resistance to PRMT5-targeted therapy in B-cell lymphoma. Moreover, combining PRMT5 inhibition with MSI2 or BCL-2 inhibitors blocks the translation of key drivers of lymphoma, c-MYC and BCL-2, inhibiting cell growth.
- Tatiana Erazo
- , Chiara M. Evans
- & Michael G. Kharas
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Article
| Open AccessGraphdiyne 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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Article
| Open AccessIntegrated 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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Article
| Open AccessOncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma
RAS mutations are commonly found in multiple myeloma (MM). Here, the authors show that oncogenic RAS mutations activate mTORC1 signalling in MM and combining mTORC1 and MEK/ERK inhibitors synergize to improve survival in preclinical models.
- Yandan Yang
- , Arnold Bolomsky
- & Ryan M. Young
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Article
| Open AccessEpigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia
Different molecular subtypes defined by specific gene rearrangements have been described for acute lymphoblastic leukaemia (ALL). Here, the authors show that ZNF384 fusion activates FLT3 expression conferring a therapeutic vulnerability for ZNF384- rearranged ALL subtype.
- Xujie Zhao
- , Ping Wang
- & Jun J. Yang
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Article
| Open AccessInterleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm
Chronic inflammation is frequently observed in patients with myeloproliferative neoplasms (MPN). Here the authors observe elevated levels of IL-1α and IL-1β in MPN patients and show that IL-1 contributes to clonal expansion and bone marrow fibrosis in a mouse model of MPN, proposing targeting of IL1R1 as therapeutic intervention.
- Mohammed Ferdous-Ur Rahman
- , Yue Yang
- & Golam Mohi
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Article
| Open AccessInhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm
Inflammatory cytokines are elevated in patients with myeloproliferative neoplasms (MPN). Here the authors show that the JAK2-V617F mutation is associated with increased expression of IL-1 in MPN patients and that loss of IL-1β in JAK2-V617F mutant hematopoietic cells reduces MPN symptoms and myelofibrosis in a mouse model.
- Shivam Rai
- , Elodie Grockowiak
- & Radek C. Skoda
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Article
| Open AccessCAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies
The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
- Yongxian Hu
- , Jingjing Li
- & He Huang
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Article
| Open AccessGermline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.
- Derek W. Brown
- , Weiyin Zhou
- & Mitchell J. Machiela
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Article
| Open AccessMulti-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
- Tomoya Isobe
- , Masatoshi Takagi
- & Junko Takita
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Comment
| Open AccessPaving the way to improve therapy for Myeloproliferative Neoplasms
Long-acting IFNα induces durable molecular responses in myeloproliferative neoplasms. Emerging studies, including Saleiro et al. recently published in Nature Communications, have identified promising candidates that may synergise with IFNα by targeting stem cell function or feedback loops that mediate treatment resistance.
- Megan Bywater
- & Steven W. Lane
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Article
| Open AccessA lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy
Combination therapies simultaneously inhibiting different therapeutic targets in cancer is challenged by individual pharmacokinetic profiles. Here, the authors generate an orally provided multi-targeted kinase inhibitor that is lymphatic absorbed and increases survival in a murine model of myelofibrosis.
- Brian D. Ross
- , Youngsoon Jang
- & Marcian E. Van Dort
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Article
| Open AccessResistance 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 AccessGeneration of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
Modelling of aggressive lymphomas, such as double hit lymphoma, has been challenging. Here the authors engineer a CRISPR activation mouse to enable the generation of these aggressive lymphomas and identify the pro-survival BCL-2 protein A1 as a venetoclax resistance factor.
- Yexuan Deng
- , Sarah T. Diepstraten
- & Marco J. Herold
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Article
| Open AccessUnified 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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Article
| Open AccessThe spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
Spatially and temporally resolved data can improve our understanding of evolution and treatment resistance in multiple myeloma (MM). Here, the authors analyse spatial and longitudinal heterogeneity in MM patients using multi-region sequencing, and identify subclones associated with relapse and therapy resistance.
- Leo Rasche
- , Carolina Schinke
- & Niels Weinhold
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Article
| Open AccessAn acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis
The oxysterol-binding protein-related protein 4 (ORP4L) is expressed in T-cell acute lymphoblastic leukemia and is required for leukemogenesis. Here the authors show that ORP4L orchestrates the transport of the phospholipid PI(4)P from Golgi to the plasma membrane, contributing to PI3K/AKT hyperactivation and T-cell leukemogenesis.
- Wenbin Zhong
- , Weize Lin
- & Daoguang Yan
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Article
| Open AccessT cell receptor β-chain-targeting chimeric antigen receptor T cells against T cell malignancies
Healthy T cells are polyclonal, while malignant T cells are developing via clonal expansion. Here authors show that T cell tumours could be eradicated by chimeric antigen receptor T cells targeting the T cell receptor (TCR) β-chain that is specific to malignant T cells, while healthy T cells using diverse TCR β-chains are spared.
- Fanlin Li
- , Huihui Zhang
- & Xuanming Yang
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Article
| Open AccessDiscovering the drivers of clonal hematopoiesis
Identifying the genetic drivers of clonal haematopoiesis (CH) has been challenging due to their low frequencies and a lack of adequate tools. Here, the authors use a reverse calling to detect blood somatic mutations and the IntOGen pipeline to identify CH drivers in large cancer genomics data sets based on signals of positive selection.
- Oriol Pich
- , Iker Reyes-Salazar
- & Nuria Lopez-Bigas
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Article
| Open AccessThe surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance
The myeloma cell surface proteome regulates plasma cell biology and delineates therapy targets. Here, the authors profile the myeloma surfaceome at baseline and in drug resistance, finding the potential target CCR10, and include a streamlined approach to primary sample analysis.
- Ian D. Ferguson
- , Bonell Patiño-Escobar
- & Arun P. Wiita
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Article
| Open AccessBlocking glycine utilization inhibits multiple myeloma progression by disrupting glutathione balance
The bone tumour microenvironment plays an essential role in multiple myeloma (MM) development. Here, the authors show that bone collagen degradation provides glycine to support MM progression through glutathione and purine synthesis.
- Jiliang Xia
- , Jingyu Zhang
- & Wen Zhou
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Article
| Open AccessClinical relevance of molecular characteristics in Burkitt lymphoma differs according to age
Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.
- Birgit Burkhardt
- , Ulf Michgehl
- & Georg Lenz
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Article
| Open AccessThe 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 AccessEndowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing
Host versus graft reaction is a major impediment to CAR-T cell immune therapy in allogeneic settings. Authors show here that CAR-T cells, engineered to be deficient in MHC I expression but to express the NK inhibitor HLA-E, are resistant to destruction by both T and NK cells of the host.
- Sumin Jo
- , Shipra Das
- & Julien Valton
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Article
| Open AccessThe genetic heterogeneity and drug resistance mechanisms of relapsed refractory multiple myeloma
The genetic factors involved in disease progression and drug resistance in multiple myeloma (MM) are varied and complex. Here, genomic and transcriptomic profiling of 511 relapsed and refractory MM patients reveals genetic alterations in several oncogenic pathways contributing to progression and resistance to MM therapies.
- Josh N. Vo
- , Yi-Mi Wu
- & Arul M. Chinnaiyan
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Article
| Open AccessOsteocyte CIITA aggravates osteolytic bone lesions in myeloma
Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.
- Huan Liu
- , Jin He
- & Jing Yang
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Article
| Open AccessGenetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes
Existing clinical models cannot fully capture smoldering multiple myeloma (SMM) heterogeneity. Here, integration of 42 genetic alterations from 214 SMM patients using an unsupervised binary matrix factorization clustering approach results in the identification of 6 distinct molecular and clinical subtypes.
- Mark Bustoros
- , Shankara Anand
- & Irene M. Ghobrial
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Article
| Open AccessA long-acting interleukin-7, rhIL-7-hyFc, enhances CAR T cell expansion, persistence, and anti-tumor activity
Chimeric antigen receptor T cells represent a breakthrough treatment in hematologic malignancies, but insufficient level of cytotoxicity and persistence of T cells might compromise success. Authors show here that a recombinant long acting form of interleukin-7 enhances proliferation, persistence and cytotoxicity of the engineered T cells, resulting in long term disease remission.
- Miriam Y. Kim
- , Reyka Jayasinghe
- & John F. DiPersio
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Article
| Open AccessAntigen glycosylation regulates efficacy of CAR T cells targeting CD19
Loss of surface CD19 expression by leukemic cells leads to resistance and relapse to CD19-targeted CAR-T therapies. Here the authors show that loss of SPPL3 in malignant B cells results in hyperglycosylation of CD19.
- Amanda Heard
- , Jack H. Landmann
- & Nathan Singh
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Article
| Open AccessDefining TCRγδ lymphoproliferative disorders by combined immunophenotypic and molecular evaluation
Tγδ large granular lymphocyte leukemia (Tγδ LGLL) is a rare lymphoproliferative neoplasm characterized by the expansion of T large granular lymphocytes expressing γδ TCR. Here, based on deep sequencing analysis of the clonotype repertoire, the authors show that leukemic Tγδ cells are characterized by recurrent public clonotypes that are diversified between symptomatic and asymptomatic patients.
- Antonella Teramo
- , Andrea Binatti
- & Renato Zambello
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Article
| Open AccessNuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis
Ph+ and Ph-like B-ALL remain poor prognosis leukemias. VAV3, a guanine nucleotide exchange factor, is activated and overexpressed in these leukemias. Here the authors reveal that leukemic VAV3 is predominantly nuclear. Nuclear VAV3, through its guanine nucleotide exchange factor and its effector nuclear RAC2, controls the repressive transcriptional activity of the polycomb repression complex-1 via nuclear AKT/PHLPP2 regulated BMI1.
- R. C. Nayak
- , K. H. Chang
- & J. A. Cancelas
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Article
| Open AccessInhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia
Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.
- Natalia Baran
- , Alessia Lodi
- & Marina Konopleva
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Article
| Open AccessGermline 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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Article
| Open AccessThe genomic and transcriptional landscape of primary central nervous system lymphoma
Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.
- Josefine Radke
- , Naveed Ishaque
- & Frank L. Heppner
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Article
| Open AccessGut 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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Article
| Open AccessIRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma
IRF4 is a regulator of immune function, and is overexpressed in lymphoid neoplasms. Here, the authors utilise single cell RNA-seq to show the abundance of double-negative T cells in IRF4 driven zebrafish tumour models, and identify sensitivity of these tumours to BRD inhibition.
- Stella Amanda
- , Tze King Tan
- & Takaomi Sanda
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Article
| Open AccessTargeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. Here the authors characterize the anti-tumor activity of allogeneic anti-CD123 CAR-T cells in preclinical models of BPDCN.
- Tianyu Cai
- , Agnès Gouble
- & Marina Konopleva
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Article
| Open AccessAllogeneic 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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Article
| Open AccessInhibition of the succinyl dehydrogenase complex in acute myeloid leukemia leads to a lactate-fuelled respiratory metabolic vulnerability
Inhibition of specific metabolic pathways often drives metabolic adaptation. Here, the authors show that FLT3-ITD + acute myeloid leukemia cells are OXPHOS-driven, and inhibition of complex II activity results in increased lactate influx to drive respiration, which creates a targetable vulnerability.
- Ayşegül Erdem
- , Silvia Marin
- & Jan Jacob Schuringa
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Article
| Open AccessA leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.
- Gerard Llimos
- , Vincent Gardeux
- & Bart Deplancke
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Article
| Open AccessA loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways
Targeting integrin-mediated retention of malignant B cells in their protective microenvironment is an efficacious treatment for lymphoma and leukemia. Here, the authors present an unbiased loss-of-adhesion CRISPR screening method, identifying therapeutic targets for these B-cell malignancies.
- Martin F. M. de Rooij
- , Yvonne J. Thus
- & Marcel Spaargaren
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Article
| Open AccessBipartite network models to design combination therapies in acute myeloid leukaemia
Identifying effective drug combinations to treat cancer is a challenging task, either experimentally or computationally. Here, the authors develop a bipartite network modelling approach to propose drug combination strategies in acute myeloid leukaemia using patient and cell line drug screening data.
- Mohieddin Jafari
- , Mehdi Mirzaie
- & Jing Tang
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Article
| Open AccessSingle-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia
T cell large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder involving clonally expanded T cell clones and is not fully understood. Here the authors show that the rest of the immune repertoire is interconnected with the T-LGLL clonotype(s) and is more mature, cytotoxic and clonally restricted than in other cancers and autoimmune disorders.
- Jani Huuhtanen
- , Dipabarna Bhattacharya
- & Satu Mustjoki
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Article
| Open AccessDiscovery of a signaling feedback circuit that defines interferon responses in myeloproliferative neoplasms
Interferon alpha (IFNalpha) therapy is showing promising results to treat myeloproliferative neoplasms (MPNs). Here, the authors show that IFNalpha response requires ULK1 phosphorylation to induce p38-MAPK signalling but it is counteracted by ROCK1-2 activation suggesting combination therapy of IFNalpha-ROCK1-2 inhibition may improve MPNs treatment.
- Diana Saleiro
- , Jeremy Q. Wen
- & Leonidas C. Platanias
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Article
| Open AccessPhase 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