Article
|
Open Access
Featured
-
-
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
-
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
-
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
-
Article
| Open AccessIntegrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines
Childhood acute lymphoblastic leukemia is characterised by a range of genetic aberrations. Here, the authors use multi-omics profiling of ALL cell lines to connect molecular phenotypes and drug responses to provide an interactive resource of drug sensitivity.
- Isabelle Rose Leo
- , Luay Aswad
- & Rozbeh Jafari
-
Article
| Open AccessDistinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification
The genomic landscape of pediatric acute myeloid leukemia (AML) has mostly been characterised for Western populations. Here, the authors identify potential driver alterations in Chinese pediatric AML, which differ from Western populations, and propose a prognostic risk classification model.
- Ting Liu
- , Jianan Rao
- & Shuhong Shen
-
Article
| Open AccessComparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells
Clonal dynamics and selection have not been fully understood in patient-derived xenografts (PDX) of acute myeloid leukemia (AML). Here, the authors generate 160 AML-PDX models to track the clonal dynamics of primary and relapsed AML, and find selectively enriched subclones that are associated with resistance to therapy.
- Naomi Kawashima
- , Yuichi Ishikawa
- & Hitoshi Kiyoi
-
Article
| Open AccessOncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia
‘Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML.
- Moritz Binder
- , Ryan M. Carr
- & Mrinal M. Patnaik
-
Article
| Open AccessSingle-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.
- Xiangjun Liu
- , Shanzhao Jin
- & Yang Wang
-
Article
| Open AccessObesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia
Obesity has been reported to promote tumourigenesis and chemoresistance but the underlying mechanisms are not completely understood. Here, the authors show that adipocytes induce Galectin-9 (GAL-9) expression in B-acute lymphoblastic leukaemia (B-ALL) cells which leads to chemoresistance and antibody-mediated blockade of GAL-9 increases survival in preclinical B-ALL murine models.
- Miyoung Lee
- , Jamie A. G. Hamilton
- & Curtis J. Henry
-
Article
| Open AccessThe Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia
Acute myeloid leukemia (AML) is genetically a very heterogeneous disease. Here, Erdem et al. uncover heterogeneity in the metabolic landscape of AML and identify Pyruvate dehydrogenase kinase 1 (PDK1) as a targetable determinant of different metabolic states in distinct subtypes of AML.
- Ayşegül Erdem
- , Silvia Marin
- & Jan Jacob Schuringa
-
Article
| Open AccessPhosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies
No targeted therapy has been approved yet for the treatment of T cell acute lymphoblastic leukemia. Here the authors show that unbiased phosphoproteomic profiling can identify targetable kinases and guide the design of personalized combination treatments using kinase inhibitors.
- Valentina Cordo’
- , Mariska T. Meijer
- & Jules P. P. Meijerink
-
Article
| Open AccessCirculating microbial content in myeloid malignancy patients is associated with disease subtypes and patient outcomes
Circulating microbiome has been very little studied for blood malignancies. Here, the authors show specific microbiome signatures in the blood are associated with different types of myeloid malignancies and specific genetic mutations.
- Jakob Woerner
- , Yidi Huang
- & Thomas LaFramboise
-
Article
| Open AccessProteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma
Acquired resistance to immunomodulatory drugs is common in multiple myeloma patients, but rarely attributed to genetic alterations. Here, proteomic, phosphoproteomic and RNA sequencing analysis in five paired pre-treatment and relapse samples reveals a CDK6-regulated protein resistance signature.
- Yuen Lam Dora Ng
- , Evelyn Ramberger
- & Jan Krönke
-
Article
| Open AccessCytofIn enables integrated analysis of public mass cytometry datasets using generalized anchors
Challenges in batch normalization and data integration limit the comparison of existing mass cytometry datasets. Here, the authors report CytofIn that can integrate mass cytometry datasets from the public domain and reveal cellular features associated with immune oncology by analyzing five public cancer datasets.
- Yu-Chen Lo
- , Timothy J. Keyes
- & Kara L. Davis
-
Article
| Open AccessHumoral and cellular responses after a third dose of SARS-CoV-2 BNT162b2 vaccine in patients with lymphoid malignancies
Vaccination is effective in preventing severe COVID-19 symptoms. Here the authors monitor patients with hematopoietic malignancy to find the third dose of the mRNA vaccine, BNT162b2, only boosts the humoral immunity in those showing responses to 2nd dose vaccination but can induce an independent T-cell response in a fraction of seronegative patients.
- Daniel Re
- , Barbara Seitz-Polski
- & Jérôme Barrière
-
Article
| Open AccessDeciphering spatial genomic heterogeneity at a single cell resolution in multiple myeloma
Osteolytic lesions (OL) are frequent in multiple myeloma (MM), but are poorly understood. Here, the authors characterise OLs in MM patient samples using single-cell RNA-seq, revealing genes that are specifically regulated in OL compared to random bone marrow aspirates and that reflect the response to induction therapy.
- Maximilian Merz
- , Almuth Maria Anni Merz
- & Jens Hillengass
-
Article
| Open AccessAn instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia
Activating mutations in Interleukin-7 receptor alpha (IL7Ra) have been reported in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) but its role in leukaemogenesis is not clear. Here, the authors show that activation of IL7Ra in primary human hematopoietic progenitors initiates preleukaemia and cooperates with CDKN2A silencing to develop BCP-ALL.
- Ifat Geron
- , Angela Maria Savino
- & Shai Izraeli
-
Article
| Open AccessCAR T cells redirected to cell surface GRP78 display robust anti-acute myeloid leukemia activity and do not target hematopoietic progenitor cells
There is an unmet need to discover suitable targets for CAR-T therapy in patients with acute myeloid leukemia (AML). Here the authors show that GRP78, a key regulator of the unfolded protein response, is highly expressed on the surface of primary AML blasts, but not on normal lymphocytes and hematopoietic progenitor cells, and that GRP78-CAR T have anti-AML activity in preclinical models.
- Nikhil Hebbar
- , Rebecca Epperly
- & M. Paulina Velasquez
-
Article
| Open AccessEliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors
Leukemic stem cells (LSCs) in chronic myeloid leukemia are resistant to imatinib and therefore are a cause of relapse. The authors show that IRAK1/4-NF-κB-PD-L1 signaling is critical to mediate imatinib resistance in LSCs and that combining imatinib with blocking this signalling pathway can eliminate LSCs.
- Yosuke Tanaka
- , Reina Takeda
- & Toshio Kitamura
-
Article
| Open AccessGenetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma
SUMOylation is a post-translational modification that has been shown to be altered in cancer. Here, the authors show that loss of the SUMO isopeptidase SENP6 leads to unrestricted SUMOylation and genomic instability promoting lymphomagenesis and generating vulnerability to PARP inhibition.
- Markus Schick
- , Le Zhang
- & Ulrich Keller
-
Article
| Open AccessA BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers
Antigen escape represents a potential drawback of chimeric antigen receptor T cell (CAR-T) therapy targeting a single tumor-associated antigen. To reduce the risk of antigen escape, here the authors report the design and characterization of a BAFF ligand CAR-T that can recognize three different receptors (BAFF-R, BCMA and TACI), demonstrating in vitro and in vivo cytotoxicity against multiple B cell cancer models.
- Derek P. Wong
- , Nand K. Roy
- & Reshmi Parameswaran
-
Article
| Open AccessFunctional dissection of inherited non-coding variation influencing multiple myeloma risk
The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
- Ram Ajore
- , Abhishek Niroula
- & Björn Nilsson
-
Article
| Open AccessInterleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia
Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia.
- Afonso R. M. Almeida
- , João L. Neto
- & João T. Barata
-
Article
| Open AccessMetabolic drug survey highlights cancer cell dependencies and vulnerabilities
Metabolic reprogramming contributes to cancer development and progression. Here, the authors show the utility of a metabolic drug library to uncover metabolic vulnerabilities and obtain functional insights into myeloid leukemia biology.
- Tea Pemovska
- , Johannes W. Bigenzahn
- & Giulio Superti-Furga
-
Article
| Open AccessClonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia
Individual studies have been underpowered to draw clear associations between clonal heterogeneity and response to therapy in acute myeloid leukemia (AML). Here, the authors aggregate multiple AML cohorts and are able to correlate the clonal abundance of somatic mutations with clinical outcomes and drug sensitivity.
- Brooks A. Benard
- , Logan B. Leak
- & Ravindra Majeti
-
Article
| Open AccessBone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation
Niche crosstalk with Haematopoietic cells underlies normal haematopoiesis and myeloid disorders. Here the authors report a Stabilin2-Cre driver mouse with Cre-activity restricted to bone marrow sinusoidal endothelial cells, and that Stabilin2-Cre driven overactivation of b-catenin leads to erythroid differentiation defects and anaemia.
- Joschka Heil
- , Victor Olsavszky
- & Philipp-Sebastian Koch
-
Article
| Open AccessSubclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics
Relapsed/refractory multiple myeloma (RRMM) is characterized by a remarkable heterogeneity and high drug resistance. Here, the authors analyse RRMM samples by single-cell RNA-sequencing, revealing molecular features associated with high-risk chromosomal 1q-gain and changes in the tumor microenvironment.
- Stephan M. Tirier
- , Jan-Philipp Mallm
- & Karsten Rippe
-
Article
| Open AccessQuinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia
Chemoresistance and relapse are main limitations in the treatment of acute lymphoblastic leukemia (ALL). Here, the authors identify Quinacrine (QC) as a sensitizer for Cytarabine (AraC) and establish a QC-CASIN regimen to improve leukemia eradication in ALL.
- Limei Wu
- , Srinivas Chatla
- & Wei Du
-
Article
| Open AccessDevelopment of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
Simultaneous targeting of BCL-xL and BCL-2 is an attractive approach for cancer treatment. Based on information gained by computational structure modelling, the authors develop a PROTAC that induces degradation of both BCL-xL and BCL-2 and effectively targets BCL-xL/2-dependent leukaemia cells.
- Dongwen Lv
- , Pratik Pal
- & Daohong Zhou
-
Article
| Open AccessSingle-cell analysis identifies dynamic gene expression networks that govern B cell development and transformation
The characterisation of B cell progenitors could benefit from single cell RNA analysis. Here the authors show distinct transcriptional profiles of B cell progenitors which are dependent upon pre-BCR and these profiles can be related to B cell transformation in lymphoblastic leukaemia.
- Robin D. Lee
- , Sarah A. Munro
- & Michael A. Farrar
-
Article
| Open AccessA human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
It is unknown why infant acute lymphoblastic leukemia (ALL) produced by MLL rearrangements leads to worse outcomes than childhood ALL. Here the authors develop a CRISPR-Cas9-induced human xenograft model of MLL-AF4 infant-ALL that faithfully replicates the disease and reveals that fetal-specific genes are potential infant-ALL drivers.
- Siobhan Rice
- , Thomas Jackson
- & Anindita Roy
-
Article
| Open AccessImmune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.
- Darci Phillips
- , Magdalena Matusiak
- & Garry P. Nolan
-
Article
| Open AccessAcute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy
Differentiation therapy induces the maturation and clearance of acute myeloid leukemia cells. Here, using a mouse model, the authors show that a specific lineage of mature leukemia-derived cells persists during remission and is responsible for disease relapse.
- Steven Ngo
- , Ethan P. Oxley
- & Ross A. Dickins
-
Article
| Open AccessDeciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses
DNA barcoding is a promising technology for the simultaneous analysis of genetic and phenotypic heterogeneity. Here, the authors combine DNA barcoding and single-cell RNA-seq to study heterogeneity, progression and response to therapy in B-cell acute lymphoblastic leukaemia patient-derived xenografts.
- Humberto Contreras-Trujillo
- , Jiya Eerdeng
- & Rong Lu
-
Article
| Open AccessDiscovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells
CRISPR-based knockout screens in cancer cells have suggested the existence of proliferation suppressor genes (PSG). Here, the authors develop an approach to systematically identify them, and reveal a PSG module involved in fatty acid synthesis and tumour suppression in acute myeloid leukemia cell lines.
- W. Frank Lenoir
- , Micaela Morgado
- & Traver Hart
-
Article
| Open AccessDemethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia
The success of CAR-T cells for treating acute myeloid leukaemia (AML) is hampered by toxicity to normal cells and low CAR-T cell persistence. Here, the authors show that the demethylating compound 5′-Azacitdine increases anti-CD123 CAR-T cell cytotoxicity against AML.
- Nadia El Khawanky
- , Amy Hughes
- & Robert Zeiser
-
Article
| Open AccessLongitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression
The molecular programs that underlie progression in multiple myeloma (MM) are incompletely understood. Here the authors use a mouse model of MM and single-cell RNA-seq to define subclonal expression programs that arise during progression and that inform targeted therapeutic strategies.
- Danielle C. Croucher
- , Laura M. Richards
- & Suzanne Trudel
-
Article
| Open AccessRare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia
Some genes that are part of balanced translocations are reported as drivers for tumourigenesis. Here, the authors report a translocation involving MTCP1 in chronic lymphocytic leukemia and show that MTCP1 overexpression leads to the disease in a murine model.
- Janek S. Walker
- , Zachary A. Hing
- & Rosa Lapalombella
-
Article
| Open AccessConvergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation
Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.
- Yuxuan Liu
- , Zhimin Gu
- & Jian Xu
-
Article
| Open AccessGenome-wide association study identifies susceptibility loci for acute myeloid leukemia
Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
-
Article
| Open AccessBone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo
Bone marrow-derived mesenchymal stroma cells (MSCs) in myeloid neoplasia have been hypothesized to carry somatic mutations and contribute to pathogenesis. Here the authors analyse ex-vivo cultures and primary MSCs derived from patients with myelodysplastic syndromes, finding functional alterations but no evidence of clonal mutations.
- Johann-Christoph Jann
- , Maximilian Mossner
- & Daniel Nowak
-
Article
| Open AccessTargeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance
miR-126 is highly expressed in inv(16) Acute myeloid leukemia (AML) but its role is unclear. Here, the authors show that the aberrant expression of miR-126 in inv(16) AML is directly due to the CBFB-MYH11 fusion gene and that it can promote AML development and leukemia stem cell maintenance, highlighting miR-126 as a therapeutic target for inv(16) AML patients
- Lianjun Zhang
- , Le Xuan Truong Nguyen
- & Ya-Huei Kuo
-
Article
| Open AccessInhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
Azacitidine (AZA) treatment is used for patients with myelodysplasias that cannot undergo bone marrow transplantation; however, AZA treatment is only partially effective. Here the authors show synergy of AZA with compounds inhibiting the chromatin regulators CBP and p300, which is mediated by the RNA-dependent functions of AZA affecting protein translation.
- Jeannine Diesch
- , Marguerite-Marie Le Pannérer
- & Marcus Buschbeck
-
Article
| Open AccessTET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.
- Morten Tulstrup
- , Mette Soerensen
- & Kirsten Grønbæk
-
Article
| Open AccessSingle cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy
The response rate of relapsed/refractory acute myeloid leukemia patients to PD-1 checkpoint blockade is low and unpredictable. Authors here show by single cell RNA sequencing, T cell receptor profiling and genomic analysis that the phenotypes and repertoire of CD8 + T cells and loss of chromosome 7/7q are important determinants of response.
- Hussein A. Abbas
- , Dapeng Hao
- & Andrew Futreal
-
Article
| Open AccessThe leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
Chromosome rearrangements can be a cause of altered oncogene expression in cancer, such as a 3q26 translocation in some acute myeloid leukemias (AML) that leads to overexpression of EVI1. Here the authors engineer this rearrangement in a cell line and show that EVI1 overexpression is a result of ‘enhancer hijacking’ of the MYC superenhancer, which is facilitated by CTCF-mediated loops.
- Sophie Ottema
- , Roger Mulet-Lazaro
- & Ruud Delwel
-
Article
| Open AccessIn vivo inducible reverse genetics in patients’ tumors to identify individual therapeutic targets
Preclinical molecular models are useful that mimic a patient´s response to targeted therapy. Here, the authors establish an in vivo inducible RNAi-mediated gene silencing system in patient-derived xenograft models of acute leukemia to identify individual vulnerabilities and therapeutic targets.
- Michela Carlet
- , Kerstin Völse
- & Irmela Jeremias
-
Article
| Open AccessTargeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies
Cancer cells proliferate and invade via cytoskeletal proteins such as WASp, exclusively expressed in hematopoietic cells. Here the authors show a specific small molecule compound inhibiting cancer cell activity by WASp degradation and demonstrating its therapeutic potential in vitro and in vivo.
- Guy Biber
- , Aviad Ben-Shmuel
- & Mira Barda-Saad
-
Article
| Open AccessSuper-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.
- Huan-Chang Liang
- , Mariantonia Costanza
- & Olaf Merkel