Haematological cancer articles within Nature Communications

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  • Article
    | Open Access

    B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.

    • Jayaram Vijayakrishnan
    • , Maoxiang Qian
    •  & Jun J. Yang

  • Article
    | Open Access

    The oncogenic fusion protein AML1-ETO has the ability of AML1 to interact with DNA but blocks AML1-dependent transcription. Here the authors report that histone lysine methyltransferase EZH1 interacts with AML1-ETO and methylates AML1-ETO at lysine 43, promoting AML1-ETO transcriptional repression in leukemia.

    • Liping Dou
    • , Fei Yan
    •  & Li Yu

  • Article
    | Open Access

    AML1-ETO is a fusion protein in which acetylation of lysine-43 is critical to leukemogenesis. Here, they show that TAF1 is required for AML1-ETO mediated gene expression such that it binds to acetylated AML1-ETO to facilitate the association of AML1-ETO with chromatin, and consequently, promotes leukemic self-renewal.

    • Ye Xu
    • , Na Man
    •  & Stephen Nimer

  • Article
    | Open Access

    In multiple myeloma, a 4;14 translocation induces overexpression of histone methyltransferase NSD2, resulting in expansion of H3K36me2 and shrinkage of H3K27me3 domains. Here the authors find that CTCF, H3K27ac and gene expression changes cluster within a subset of insulated domains implicating 3D chromosome organization as a key factor in the NSD2-mediated phenotype.

    • Priscillia Lhoumaud
    • , Sana Badri
    •  & Jane A. Skok

  • Article
    | Open Access

    Cyclin-dependent kinases are deregulated in blood cancers. Here, the authors show that CDK8, independent of its kinase activity, regulates mTOR signalling for the maintenance of BCR-ABL1+ leukemia, and that the dual inhibition of CDK8 and mTOR signalling induces apoptosis in these cells.

    • Ingeborg Menzl
    • , Tinghu Zhang
    •  & Veronika Sexl

  • Article
    | Open Access

    Promyelocytic leukemia protein (PML) is the scaffolding protein that organizes PML nuclear bodies. Here the authors determine the crystal structure of a PML B1-box multimer and characterise the oligomerisation behaviour of the PML RBCC construct and show that disrupting B1-B1 interactions precludes promyelocytic leukemia leukemogenesis in transgenic mice.

    • Yuwen Li
    • , Xiaodan Ma
    •  & Guoyu Meng

  • Article
    | Open Access

    The advent of single-cell RNA sequencing has revealed significant transcriptional heterogeneity in cancer, but its relationship to genomic heterogeneity remains unclear. Focusing on acute myeloid leukemia samples, the authors describe a general approach for linking mutation-containing cells to their transcriptional phenotypes using single-cell RNA sequencing data.

    • Allegra A. Petti
    • , Stephen R. Williams
    •  & Timothy J. Ley

  • Article
    | Open Access

    The definition of regulatory landscape at chronic lymphocytic leukaemia (CLL) risk loci is limited. Here, the authors perform an epigenomic characterisation of 42 known risk loci in CLL and normal B cells at different developmental stages and show active chromatin and target genes in the risk loci.

    • Helen E. Speedy
    • , Renée Beekman
    •  & José I. Martín-Subero

  • Article
    | Open Access

    Mutational signature analysis provides important information about the mutational processes underpinning different stages of tumorigenesis. Here, the authors compare publicly available signature extraction tools and suggest a framework for the generation of accurate and reproducible signature data.

    • Francesco Maura
    • , Andrea Degasperi
    •  & Niccolò Bolli

  • Article
    | Open Access

    There is increasing evidence that epigenetic mechanisms contribute to therapeutic resistance in cancer. Here the authors study AML patient samples and a mouse model of non-genetic resistance and find that transcriptional plasticity drives stable epigenetic resistance, and identify regulators of enhancer function as important modulators of resistance.

    • Charles C. Bell
    • , Katie A. Fennell
    •  & Mark A. Dawson

  • Article
    | Open Access

    NPM1 gene mutation is a founding event in acute myeloid leukaemia. Here, the authors find that at relapse, some patients lose the NPM1 mutation and show distinct mutational and gene expression patterns, highlighting a potential route for relapse.

    • Sibylle Cocciardi
    • , Anna Dolnik
    •  & Konstanze Döhner

  • Article
    | Open Access

    Multiple myeloma is frequently characterised by translocation of genes next to the immunoglobulin heavy chain locus. In this study, the authors sequence a large cohort of high risk myeloma samples and find translocations of cMyc to the immunoglobulin heavy chain locus and this is associated with poor prognosis.

    • Benjamin G. Barwick
    • , Paola Neri
    •  & Lawrence H. Boise

  • Article
    | Open Access

    In chronic lymphocytic leukemia (CLL), evolution is driven by transcriptional and epigenetic heterogeneity. Here, the authors integrate epigenomic analyses to show how intra-tumoral epigenetic diversity results in divergent chromatin states in CLL cells, increasing cell-to-cell transcriptional heterogeneity.

    • Alessandro Pastore
    • , Federico Gaiti
    •  & Dan A. Landau

  • Article
    | Open Access

    Translocation of (6;8)(p21;q24), a recurrent abnormality of blastic plasmacytoid dendritic cell neoplasm, involves adjacent MYC and RUNX2 regions. Here, the authors show that the RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, promoting the development of this cancer.

    • Sho Kubota
    • , Kenji Tokunaga
    •  & Goro Sashida

  • Article
    | Open Access

    High hyperploidy is a common feature in childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors perform proteogenomic and Hi-C analyses of this leukemia and the ETV6/RUNX1 subtype and show that CTCF and cohesin expression are low in hyperdiploid cases and transcriptional dysregulation in relation to topologically associating domain borders in some of these cases.

    • Minjun Yang
    • , Mattias Vesterlund
    •  & Kajsa Paulsson

  • Article
    | Open Access

    Identification of cancer genes altered by non-genetic mechanisms in B-cell lymphoma is challenging. Here, the authors report the development of transposon tools to perform genome-wide recessive screens in vivo and validate identified putative tumor suppressor genes using a CRISPR/Cas9 validation platform.

    • Julia Weber
    • , Jorge de la Rosa
    •  & Roland Rad

  • Article
    | Open Access

    Allogeneic hematopoietic cell transplantation is the standard treatment of acute myeloid leukemia, but many patients relapse. Here the authors show increased markers of exhaustion and cancer antigen specificity within bone marrow-residing memory T cells precede and potentially predict the relapse.

    • Maddalena Noviello
    • , Francesco Manfredi
    •  & Chiara Bonini

  • Article
    | Open Access

    BCL6 corepressor (BCOR) is recurrently mutated in acute myeloid leukaemia and myelodysplastic syndrome. Here, the authors use mouse models to show the mechanism of how inactivation of BCOR in haematopoietic stem cells contributes to the development of leukaemia.

    • Madison J. Kelly
    • , Joan So
    •  & Lev M. Kats

  • Article
    | Open Access

    Somatic heterozygous TET2 loss drives clonal hematopoiesis, which is linked to malignant cell degeneration and potentially cardiovascular disease. Here, the authors investigate the molecular impact of a germline TET2 mutation in a lymphoma family, finding elevated blood DNA methylation levels and no predisposition to atherosclerosis

    • Eevi Kaasinen
    • , Outi Kuismin
    •  & Lauri A. Aaltonen

  • Article
    | Open Access

    Myelodyplastic hematopoietic stem cells (MDS HSC) have eluded in vivo modeling. Here the authors present a highly efficient MDS patient-derived xenotransplantation model in cytokine-humanized mice with replication of the donors’ genetic complexity and myeloid, erythroid, and megakaryocytic lineage dysplasia.

    • Yuanbin Song
    • , Anthony Rongvaux
    •  & Stephanie Halene

  • Article
    | Open Access

    FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.

    • Haijiao Zhang
    • , Samantha Savage
    •  & Jeffrey W. Tyner

  • Article
    | Open Access

    Splicing factors are often mutated in hematological malignancies. Here, the authors perform an in vivo shRNA screen in a CEBPA mutant AML mouse model and identify that RBM25 controls the splicing of pre-mRNAs encoding BCL-X and BIN1 to exert its tumour suppressor activities in AML.

    • Ying Ge
    • , Mikkel Bruhn Schuster
    •  & Bo Torben Porse

  • Article
    | Open Access

    High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

    • Adriana E. Tron
    • , Matthew A. Belmonte
    •  & Alexander W. Hird

  • Article
    | Open Access

    Acute myeloid leukaemia (AML) affects people of all ages. Here, the authors model AML in vivo and demonstrate that the age of the cell of origin impacts leukaemia development and the genetic signature where adult cells of origin give rise exclusively to AML and young cells of origin give rise to myeloid, lymphoid or mixed phenotype acute leukaemia.

    • Shahzya Chaudhury
    • , Caitríona O’Connor
    •  & Karen Keeshan

  • Article
    | Open Access

    The mechanisms through which gut microbiota affect extramucosal tumors are poorly understood. Here the authors show that the gut microbiota promotes multiple myeloma by inducing differentiation and migration of Th17 cells in the bone marrow resulting also in increased recruitment of pro-tumorigenic eosinophils.

    • Arianna Calcinotto
    • , Arianna Brevi
    •  & Matteo Bellone

  • Article
    | Open Access

    Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.

    • Mary L. McMaster
    • , Sonja I. Berndt
    •  & Neil E. Caporaso

  • Article
    | Open Access

    The Wnt pathway is one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL) and is activated in only a subset of patients; however, no universal drivers of the disease have been identified. Here the authors show that Notch2 and β-catenin pathways are the main drivers of the pro-survival bidirectional crosstalk between stromal cells and leukemic cells.

    • Maurizio Mangolini
    • , Frederik Götte
    •  & Ingo Ringshausen

  • Article
    | Open Access

    Multiple myeloma is a cancer of the plasma cells, and the complete aetiology of the disease is still unclear. Here the authors perform an additional GWAS analysis followed by a meta-analysis with existing GWAS and replication genotyping and identify 6 novel risk loci and utilise gene expression, epigenetic profiling and in situ Hi-C data to further our understanding of MM susceptibility.

    • Molly Went
    • , Amit Sud
    •  & Stephen N. Thibodeau

  • Article
    | Open Access

    The mechanism underlying the dissemination of diffuse large B-cell lymphoma (DLBCL) is unclear. Here, the authors show that STAT3 controls amoeboid migration in DLBCL via the transcriptional activation of RHOH, which then releases RhoA from RhoGDIγ-mediated suppression, or via regulating microtubule dynamics to activate RhoA.

    • Yi-Ru Pan
    • , Chih-Cheng Chen
    •  & Muh-Hwa Yang

  • Article
    | Open Access

    Smoldering MM (SMM) is a premalignant stage of multiple myeloma (MM). Here the authors perform whole genome sequencing of unique paired samples of SMM progressing to MM, and show that the genomic landscape at the SMM stage is very similar to MM, but trajectories of evolution can vary from patient to patient.

    • Niccolò Bolli
    • , Francesco Maura
    •  & Nikhil Munshi

  • Article
    | Open Access

    ASXL1 gene is often mutated in myeloid malignancies. Here, the authors show that mutant ASXL1 and BAP1 are in a positive feedback loop such that BAP1 induces monoubiquitination of mutant ASXL1, which in turn enhances BAP1 activity to potentiate myeloid transformation via HOXA clusters and IRF8.

    • Shuhei Asada
    • , Susumu Goyama
    •  & Toshio Kitamura

  • Article
    | Open Access

    UTX is a tumor suppressor gene located on the X-chromosome so it could potentially contribute to the cancer gender bias. Here the authors, using a mouse model of B cell lymphoma, show that UTX is a dosage sensitive tumor suppressor and may be responsible for some of the increased incidence and possibly aggressiveness of male cancers that harbour UTX mutations.

    • Xiaoxi Li
    • , Yanli Zhang
    •  & Hai Jiang

  • Article
    | Open Access

    Myelodysplastic syndrome (MDS) is characterized by altered hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) regulation and reduction of miR-143 and miR-145 in some subtypes. Here the authors show that miR-143/145 loss leads to HSC depletion, HPC expansion and malignancy through Dab2 -mediated TGFβ pathway activation.

    • Jeffrey Lam
    • , Marion van den Bosch
    •  & Aly Karsan

  • Article
    | Open Access

    In leukemia, diverse fusion proteins involving the MLL gene can drive oncogenic activity. Here, the authors describe a dependency of MLL-leukemia cells on the methyltransferase SETD2 to maintain genomic integrity during leukemia initiation and maintenance.

    • Anna Skucha
    • , Jessica Ebner
    •  & Florian Grebien

  • Article
    | Open Access

    The stromal microenvironment plays a key role in the expansion of chronic lymphocytic leukemia. Here, the authors use the Eµ-TCL1 mouse model to show that leukemic B-cells induce the activation of retinoic acid synthesis in stromal cells of the lymphoid microenvironment, and that impacting on retinoic acid signalling via diet or chemical inhibition prolonged survival by preventing leukemia dissemination and accumulation in lymphoid tissues.

    • Diego Farinello
    • , Monika Wozińska
    •  & Andrea Brendolan

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