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Transcriptomic 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 Access
LYN 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 Access
Molecular 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 Access
Dysregulation 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 Access
Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape
NOTCH mutations are frequent in B cell malignancies. Here the authors use retroviral transduction of primary malignant B cells from Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL) patients to show that NOTCH1/2-mutations facilitate mechanism of immune escape.
- Maurizio Mangolini
- , Alba Maiques-Diaz
- & Ingo Ringshausen
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Article
| Open Access
Proteogenomics 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 Access
Defining 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 Access
A 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 Access
Rare 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
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Article
| Open Access
Multi-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
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Article
| Open Access
Targeted 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
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Article
| Open Access
Genome-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
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| Open Access
Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL
Ibrutinib, a Bruton tyrosine kinase inhibitor, provides effective treatment for chronic lymphocytic leukemia (CLL). Here, the authors describe time-dependent molecular changes to malignant cells and to the immune system in patients undergoing ibrutinib therapy, with can be used for therapy monitoring.
- André F. Rendeiro
- , Thomas Krausgruber
- & Christoph Bock
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Article
| Open Access
Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics
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
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Article
| Open Access
Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL
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
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Article
| Open Access
Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia
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
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Article
| Open Access
A retinoic acid-dependent stroma-leukemia crosstalk promotes chronic lymphocytic leukemia progression
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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| Open Access
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.
- Carmen D. Herling
- , Nima Abedpour
- & Martin Peifer
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Article
| Open Access
NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia
NFAT2 is a transcription factor that has been linked with chronic lymphocytic leukaemia (CLL), but its functions in CLL manifestation are still unclear. Here the authors show, by analysing mouse CLL models and characterising biopsies from CLL patients, that NFAT2 is an important regulator for the anergic phenotype of CLL.
- Melanie Märklin
- , Jonas S. Heitmann
- & Martin R. Müller
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| Open Access
Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia
ATM and TP53 mutations are associated with poor prognosis in chronic lymphocytic leukaemia (CLL). Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.
- Gero Knittel
- , Tim Rehkämper
- & H. Christian Reinhardt
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Article
| Open Access
Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) is characterized by cell-autonomous B-cell receptor (BcR)-mediated signalling of neoplastic B lymphocytes. Here the authors unveil the structural basis and diversity of activatory homotypic BcR contacts and link them with CLL heterogeneity and the clinical outcome.
- Claudia Minici
- , Maria Gounari
- & Massimo Degano
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Article
| Open Access
Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia
Disease monitoring of chronic lymphocytic leukaemia (CLL) is a challenge. Here, the authors show that serial ctDNA analysis in 32 CLL patients allows monitoring of clonal dynamics over time, and identifies the emergence of genomic changes associated with Richter’s syndrome.
- Paul Yeh
- , Tane Hunter
- & Sarah-Jane Dawson
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Article
| Open Access
Evolution of multiple cell clones over a 29-year period of a CLL patient
Studying the genetic progression of many cancers is difficult as longitudinal samples are rarely available. Here, the authors analyse a patient with chronic lymphocytic leukaemia over a 29 year period and track the clonal evolution of the patient’s disease and response to therapy.
- Zhikun Zhao
- , Lynn Goldin
- & Michael Dean
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Article
| Open Access
Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks
Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity. Here, the authors report the genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using ATAC-seq, and 10 matched RNA-seq datasets, providing a resource for studying epigenome deregulation in CLL.
- André F. Rendeiro
- , Christian Schmidl
- & Christoph Bock
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Article
| Open Access
Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition
The BTK inhibitor ibrutinib is used to treat chronic lymphocytic leukaemia, however some patients develop resistance to the drug. Here, the authors use genomic analyses to examine the clonal evolution of 5 patients that develop resistance to ibrutinib.
- Jan A. Burger
- , Dan A. Landau
- & Catherine J. Wu
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Article
| Open Access
Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPPassociated with risk of this disease.
- Sonja I. Berndt
- , Nicola J. Camp
- & Susan L. Slager
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Article
| Open Access
Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
The oncogenic events driving indolent chronic lymphocytic leukaemia are relatively unknown. Here, the authors perform whole genome sequencing on 30 such tumours and identify recurrent mutations in IGLL5and two activation induced cytidine deaminase signatures that are operative at different stages of CLL evolution.
- S. Kasar
- , J. Kim
- & J. R. Brown
Mutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia