Featured
-
-
Article
| Open AccessChromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma
Despite extensive genetic heterogeneity, nearly half of all multiple myeloma (MM) cases are driven by cyclin D2 (CCND2) over-expression. Here the authors dissect the chromatin landscape of MM to provide insights into the transcriptional regulatory landscape driving MM and divergent transcriptomes corresponding to different MM genetic subtypes.
- Jaime Alvarez-Benayas
- , Nikolaos Trasanidis
- & Anastasios Karadimitris
-
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
-
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
-
Article
| Open AccessMolecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.
- Fabian Frontzek
- , Annette M. Staiger
- & Georg Lenz
-
Article
| Open AccessCopy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma
Chromothripsis is associated with unfavourable outcomes in multiple myeloma (MM), but its detection usually requires whole genome sequencing. Here the authors develop an approach to detect chromothripsis in MM based on copy-number signatures that also works with whole exome sequencing data.
- Kylee H. Maclachlan
- , Even H. Rustad
- & Francesco Maura
-
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
-
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
-
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
-
Article
| Open AccessChronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma
Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.
- Makoto Yamagishi
- , Miyuki Kubokawa
- & Kaoru Uchimaru
-
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
-
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
-
Article
| Open AccessFusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified
Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.
- Koen Debackere
- , Lukas Marcelis
- & Daan Dierickx
-
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
-
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
-
Article
| Open AccessRobust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing
Preservation of cancer biopsies by FFPE introduces DNA fragmentation, hindering analysis of rearrangements. Here the authors introduce FFPE Targeted Locus Capture for identification of translocations in preserved samples.
- Amin Allahyar
- , Mark Pieterse
- & Wouter de Laat
-
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
-
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
-
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
-
Article
| Open AccessLongitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma
Mantle cell lymphoma can be refractory to treatment. Here, the authors used single cell sequencing to study the tumours of patients that were responsive and resistant to treatment and find gains of 17q in resistant tumours, which they attribute to increased expression of Birc5 and validate these findings in mouse models of the disease.
- Shaojun Zhang
- , Vivian Changying Jiang
- & Michael Wang
-
Article
| Open AccessClonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
In chronic myeloid leukaemia (CML), the drivers of blast crisis and resistance to tyrosine kinase inhibitors are not fully characterised. Here, the authors analyse a cohort of CML samples with genomic technologies and find that at least one driver alteration is associated with progression and worse prognosis.
- Yotaro Ochi
- , Kenichi Yoshida
- & Lee-Yung Shih
-
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
-
Article
| Open AccessCo-evolution of tumor and immune cells during progression of multiple myeloma
Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.
- Ruiyang Liu
- , Qingsong Gao
- & Li Ding
-
Article
| Open AccessMastocytosis-derived extracellular vesicles deliver miR-23a and miR-30a into pre-osteoblasts and prevent osteoblastogenesis and bone formation
Osteoporosis and bone disease are common in patients with systemic mastocytosis. Here, the authors show that extracellular vesicles released by neoplastic mast cells of the patients block osteoblast differentiation and bone mineralization when injected into mice, via a mechanism involving suppression of osteogenic factors via miRNA-30a and miRNA-23a.
- Do-Kyun Kim
- , Geethani Bandara
- & Ana Olivera
-
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
-
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
-
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
-
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
-
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
-
Article
| Open AccessWhole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities
The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient’s life.
- Bénedith Oben
- , Guy Froyen
- & Francesco Maura
-
Article
| Open AccessMutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
- Takeshi Fujino
- , Susumu Goyama
- & Toshio Kitamura
-
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
-
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
-
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
-
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
-
Article
| Open AccessTargeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma
The mechanisms behind acquired resistance to the proteasome inhibitor bortezomib in multiple myeloma remain to be elucidated. Here, the authors show that the histone methyltransferase NSD2 stabilized SRC-3 protein levels, promotes its phase separation and alters H3K36me2 at certain gene promoters resulting in a transcriptional profile that favors resistance of myeloma cells to bortezomib.
- Jing Liu
- , Ying Xie
- & Zhiqiang Liu
-
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
-
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
-
Article
| Open AccessBiallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma
Relapse following BCMA targeted CAR T-cell therapy is frequently observed in patients with multiple myeloma (MM). Here, by single cell transcriptome profiling on serially collected bone marrow samples, the authors report biallelic loss of BCMA as the mechanism of resistance underlying both relapse and lack of response to a second CAR T infusion in a patient with MM.
- Mehmet Kemal Samur
- , Mariateresa Fulciniti
- & Nikhil C. Munshi
-
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
-
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
-
Article
| Open AccessDynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation
The dynamics of genome architecture during human cell differentiation and upon neoplastic transformation remain poorly characterized. Here, the authors integrate in situ Hi-C and nine additional omic layers to characterize the dynamic changes in 3D genome architecture during normal B cell differentiation and in neoplastic cells from chronic lymphocytic leukemia and mantle cell lymphoma patients.
- Roser Vilarrasa-Blasi
- , Paula Soler-Vila
- & José Ignacio Martin-Subero
-
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
-
Article
| Open AccessAdrenomedullin-CALCRL axis controls relapse-initiating drug tolerant acute myeloid leukemia cells
Leukemic stem cells which are resistant to chemotherapy are proposed as relapse-initiating cells (RICs). Here, the authors show that targeting the adrenomedullin-calcitonin receptor-like receptor decreases RICs frequency improving chemotherapy response in AML preclinical models.
- Clément Larrue
- , Nathan Guiraud
- & Jean-Emmanuel Sarry
-
Article
| Open AccessTargeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease
Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.
- Antonio Garcia-Gomez
- , Tianlu Li
- & Esteban Ballestar
-
Article
| Open AccessCXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells
CAR-T cell therapy targeting CD19 is not as efficient to treat lymphoma with nodal dissemination as it is for B cell leukaemia. Here, the authors generate CAR-T cells against CXCR5 and show they inhibit tumour growth by depleting both B and follicular T helper cells in lymphoma models.
- Mario Bunse
- , Janina Pfeilschifter
- & Uta E. Höpken
-
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
-
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
-
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
-
Article
| Open AccessTRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation
c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.
- Ke Li
- , Feng Wang
- & Zhuo-wei Hu