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| Open AccessTET2 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 AccessDeleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.
- Yun Soo Hong
- , Stephanie L. Battle
- & Dan E. Arking
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Article
| Open AccessThe 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 AccessDisentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study
Multiple myeloma (MM) is a haematological malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS). Here, the authors use a mechanistic model fitted to surveillance data from the United States to investigate whether variation in MM is best explained by incidence of MGUS or rate of progression to MM.
- John H. Huber
- , Mengmeng Ji
- & Su-Hsin Chang
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| Open AccessLarge T cell clones expressing immune checkpoints increase during multiple myeloma evolution and predict treatment resistance
Myelomagenesis progresses through well-defined pre-malignant states. Here, using single-cell RNA sequencing and T cell receptor repertoire analysis of bone marrow T cells in patients at different stages of myelomagenesis, the authors identify large clonotypic expansions characterized by the expression of multiple immune checkpoints.
- Cirino Botta
- , Cristina Perez
- & Bruno Paiva
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Article
| Open AccessABCC1 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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Article
| Open AccessImmunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma
How the immune response is involved in the response to multiple myeloma after treatment is not fully understood. Here the authors investigate how lenalidomide treatment in newly diagnosed MM patients affects the immune microenvironment in the blood and bone marrow and compare between responses to treatment.
- David G. Coffey
- , Francesco Maura
- & Ola Landgren
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Article
| Open AccessAcquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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Article
| Open AccessMLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
- Nicholas T. Crump
- , Alastair L. Smith
- & Thomas A. Milne
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Article
| Open AccessImmune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice
Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.
- Marta Isidro-Hernández
- , Ana Casado-García
- & Isidro Sánchez-García
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Article
| Open AccessPhase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency
Here, Heitmann et al. report results from a Phase I/II trial evaluating CoVac-1, a peptide-based T-cell activator, in patients with B-cell deficiency, demonstrating potent induction of SARS-CoV-2-specific T-cell responses along with a favorable safety profile.
- Jonas S. Heitmann
- , Claudia Tandler
- & Juliane S. Walz
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Article
| Open AccessResolving the spatial architecture of myeloma and its microenvironment at the single-cell level
The spatial architecture of multiple myeloma remains to be explored. Here, the authors perform bulk and single cell sequencing for samples from newly diagnosed patients and reveal gene signatures associated with focal lesions and spatial heterogeneity in the tumour microenvironment.
- Lukas John
- , Alexandra M. Poos
- & Niels Weinhold
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| Open AccessCOMPASS: 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 AccessComputational analysis of peripheral blood smears detects disease-associated cytomorphologies
While experts analyze cytomorphology to diagnose myelodysplastic syndromes, definitive diagnosis requires complementary information such as karyotype and molecular genetics testing. Here, the authors present a computational method that automatically detects, characterizes and helps identify blood cell characteristics associated with this group of diseases.
- José Guilherme de Almeida
- , Emma Gudgin
- & Moritz Gerstung
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Article
| Open AccessContext-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Co-dependency mapping assays have revealed genetic dependencies in cancer and could shed light on chromatin crosstalk mechanisms. Here, the authors establish a pipeline to integrate co-dependency mapping screens with molecular information in pan-cancer cell lines in order to reveal chromatin complexes and potential drug targets.
- Xiao Chen
- , Yinglu Li
- & Chao Lu
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Article
| Open AccessThe checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease
Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Here, the authors demonstrate that the checkpoint inhibitor PD-1H functions as a potential MMP-13 receptor on osteoclasts, mediating MMP-13 induced cytoskeleton reorganization, fusogenesis and bone resorption and further regulating osteolytic lesions.
- Jing Fu
- , Shirong Li
- & Suzanne Lentzsch
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Article
| Open AccessChimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma
Patients treated for multiple myeloma often experience relapse due to antigen loss, thus necessitating the identification of additional therapeutic targets. In this study, the authors demonstrate that FcRH5 is expressed on MM cells and can be targeted using chimaeric antigen receptor T cells in mice.
- Dongpeng Jiang
- , Haiwen Huang
- & Jianhong Chu
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Article
| Open AccessNeutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
B cell malignancies resistant to conventional treatments are potentially sensitive to CAR-T cell immune therapy, but its clinical applicability is limited by immune related adverse effects. Here authors show in a humanized mouse model that blocking IFNγ with the monoclonal antibody emapalumab mitigates the adverse effects of CAR.CD19-T cells without compromising their anti-lymphoma efficacy.
- Simona Manni
- , Francesca Del Bufalo
- & Concetta Quintarelli
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| Open AccessLeukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation
Graft-versus-leukemia reactions are required for the eradication of myeloid malignancies after allogeneic hematopoietic cell transplantation. However, treatment efficacy is variable, depending on the immunological response. Here the authors show that dysfunction of HLA heterogeneity is associated with post-transplant leukemia relapse.
- Simona Pagliuca
- , Carmelo Gurnari
- & Jaroslaw P. Maciejewski
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Article
| Open AccessMolecular 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 AccessFrom a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia
Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for antiproliferative therapies for cancers where it is essential. Here, the authors develop a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.
- Magali Saez-Ayala
- , Laurent Hoffer
- & Xavier Morelli
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Article
| Open AccessDasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Despite playing a central role the treatment of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), resistance to glucocorticoids remains a major obstacle. Here, the authors identify activation of PI3K/mTOR and CREB pathways as a driver of GC-resistance in BCP-ALL and restore sensitivity using the multi kinase inhibitor, dasatinib.
- Jolanda Sarno
- , Pablo Domizi
- & Kara L. Davis
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Article
| Open AccessTranscriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia
The CLL14 study (NCT02242942) explored the activity of obinutuzumab (anti-CD20) plus venetoclax (Bcl2 inhibitor) versus obinutuzumab plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL). Here the authors report the 5-year long-term results of the clinical trial and transcriptional profiles associated with response to therapies.
- Othman Al-Sawaf
- , Can Zhang
- & Kirsten Fischer
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Article
| Open AccessOncogenic 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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Article
| Open AccessExcessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma
The molecular mechanisms underlying the development of thrombocytopenia in multiple myeloma (MM) remain to be explored. Here, the authors show an association of thrombocytopenia with poor prognosis in MM and identify serine as a key metabolic regulator of thrombocytopenia.
- Chunmei Kuang
- , Meijuan Xia
- & Wen Zhou
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Article
| Open AccessInflammatory 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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Article
| Open AccessMOZ/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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Article
| Open AccessOncogenic CALR mutant C-terminus mediates dual binding to the thrombopoietin receptor triggering complex dimerization and activation
In myeloproliferative neoplasms, frameshift mutants of calreticulin turn into rogue cytokines by inducing constitutive activation of the Thrombopoietin Receptor (TpoR). Here, the authors define how mutant calreticulin acquires specificity for TpoR binding and triggers its constitutive activation.
- Nicolas Papadopoulos
- , Audrey Nédélec
- & Stefan N. Constantinescu
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| Open AccessTargeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Article
| Open AccessClonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
High hyperdiploid acute lymphoblastic leukaemia (HeH ALL) is driven by nonrandom chromosomal gains, which have been suggested to arise early - even before birth. Here, the authors use single-cell whole genome sequencing and in silico modelling to show that HeH ALL aneuploidies could originate early and follow punctuated evolution.
- Eleanor L. Woodward
- , Minjun Yang
- & Kajsa Paulsson
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Article
| Open AccessSynthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma
Genomic instability occurs infrequently in in diffuse large B cell lymphoma (DLBCL), suggesting a therapeutic vulnerability. Here, the authors identify a synergistic combination between the induction of polyploidy by a PLK4 inhibitor and a BCL-2 inhibitor in DLBCL.
- Ana Portelinha
- , Mariana da Silva Ferreira
- & Hans-Guido Wendel
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| Open AccessInhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies
Hypomethylating agents, such as 5-Azacytidine (5-AZA), are standard of care for patients with myelodysplastic and myeloid malignancies, however response rates are limited and risk of relapses high. Here the authors show that inhibition of lysyl oxidases synergizes with 5-AZA to improve erythropoiesis and reduce disease burden in myelodysplastic neoplasms models.
- Qingyu Xu
- , Alexander Streuer
- & Daniel Nowak
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Article
| Open AccessBET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas
Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.
- Victor Moreno
- , Maria Vieito
- & Irene Braña
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Article
| Open AccessLYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1
The survival of chronic lymphocytic leukemia cells strongly depends on the presence of a supportive microenvironment. Here, the authors show that LYN kinase is essential for the reprogramming of stromal cells towards a leukemia-supportive phenotype that facilitates disease progression.
- Alexander F. vom Stein
- , Rocio Rebollido-Rios
- & Michael Hallek
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Article
| Open AccessDeacetylation induced nuclear condensation of HP1γ promotes multiple myeloma drug resistance
The molecular mechanisms underlying acquired chemoresistance to proteasome inhibitors (PIs) in multiple myeloma (MM) remain to be explored. Here, the authors highlight the role of heterochromatin protein 1 gamma as a potential target for overcoming resistance to PIs in MM.
- Xin Li
- , Sheng Wang
- & Zhiqiang Liu
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Article
| Open AccessLongitudinal 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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Article
| Open AccessProteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia
KMT2A rearranged infant acute lymphoblastic leukemia patients have a poor prognosis. Here, the authors use high throughput drug screening on primary infant specimens to identify a clinically active chemotherapy combination.
- Jennifer L. Kamens
- , Stephanie Nance
- & Tanja A. Gruber
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Article
| Open AccessMulti-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia
The PML-RARA gene fusion is the characteristic driver of Acute Promyelocytic Leukaemia (APL) and is known to bind to the genome. Here, the authors characterise the impact of PML-RARA on gene regulation in APL cell lines and patient samples using transcriptomics, epigenomics, and machine learning.
- William Villiers
- , Audrey Kelly
- & Cameron S. Osborne
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Article
| Open AccessMyelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation
Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.
- Maxime Boy
- , Valeria Bisio
- & Nicolas Dulphy
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Article
| Open AccessChromatin complex dependencies reveal targeting opportunities in leukemia
Epigenetic regulators are potential therapeutic drug targets in leukemia. Here, the authors perform combinatorial CRISPR knockouts to test gene-gene pairings in leukemia cells to discover compensatory non-lethal or synergistic lethal combinations with therapeutic potential.
- Fadi J. Najm
- , Peter DeWeirdt
- & Bradley E. Bernstein
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Article
| Open AccessMolecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis
Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.
- Julien Broséus
- , Sébastien Hergalant
- & Stephan Stilgenbauer
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Article
| Open AccessEarly 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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Article
| Open AccessDysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation
Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.
- Zachary A. Hing
- , Janek S. Walker
- & Rosa Lapalombella
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Article
| Open AccessEndogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation
Enhanced IL-1β signaling pathway causes hematopoietic stem cell (HSC) to differentiate into myeloid cells and contributes to malignant hematopoiesis. Here the authors reveal that HSC differentiation is controlled by balanced levels of IL-1 receptor antagonist (IL-1rn) and IL-1β under steady-state, and that IL-1rn protects against pre-leukemic myelopoiesis by repressing IL-1β signaling.
- Alicia Villatoro
- , Vincent Cuminetti
- & Lorena Arranz
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Article
| Open AccessModulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open AccessThe transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are age-related pathologies in which alterations of hematopoietic stem cells lead to abnormal formation of blood cells. Here, the authors study the lesions that these cells undergo in aging and disease, characterizing a factor whose alteration in MDS leads to abnormal blood cell production.
- Nerea Berastegui
- , Marina Ainciburu
- & Felipe Prosper
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Article
| Open AccessInflammatory 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 AccessRegulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability
The ETV6-RUNX1 chimeric- and native RUNX1-responsive regulomes in paediatric B-acute lymphoblastic leukemia (B-ALL) remain to be characterized. Here, the authors reveal functional antagonism between the two transcription factors predominantly for the regulation of cell cycle-associated pathways and dependency on native RUNX1 for tumorigenesis which can be targeted pharmacologically.
- Jason P. Wray
- , Elitza M. Deltcheva
- & Tariq Enver
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Article
| Open AccessSingle cell characterization of myeloma and its precursor conditions reveals transcriptional signatures of early tumorigenesis
Development of multiple myeloma is preceded by precursor conditions. Here, the authors use single cell RNA-sequencing of plasma cells from patients across disease stages to identify genomic signatures present even at the earliest stages of disease.
- Rebecca Boiarsky
- , Nicholas J. Haradhvala
- & Gad Getz