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| Open AccessGlucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling
Resistance to glucocorticoids (GC) is a major obstacle for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Here, the authors report that GC-triggered CXCR4 internalization promotes a phospholipase C (PLC)-mediated cell survival pathway, driving GC resistance in B-ALL.
- Souleymane Abdoul-Azize
- , Rihab Hami
- & Olivier Boyer
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Article
| Open AccessInvestigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
The effect of noncoding genetic variation on acute lymphoblastic leukemia treatment response is not fully understood. Here, the authors functionally evaluated variants associated with pharmacological traits and validate the role of rs1247117 in gene regulation impacting therapeutic response.
- Kashi Raj Bhattarai
- , Robert J. Mobley
- & Daniel Savic
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Article
| Open AccessTranslation efficiency driven by CNOT3 subunit of the CCR4-NOT complex promotes leukemogenesis
Here the authors uncovered CNOT3, a subunit of the CCR4-NOT complex, as an essential modulator of translation in leukemia. The work pointed to the potential of targeting the posttranscriptional circuitry via CNOT3 as a therapeutic vulnerability in acute myeloid leukemia.
- Maryam Ghashghaei
- , Yilin Liu
- & Ly P. Vu
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Article
| Open AccessInhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
- Martha M. Zarou
- , Kevin M. Rattigan
- & G. Vignir Helgason
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Article
| Open AccessComprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies
IFNγ signaling is important in the pathogenesis and immune response, emphasizing the need for investigation of its role. Here, the authors show that IFNγ plays a key role in shaping immune microenvironment in AML and developing resistance, providing insights for potential therapeutic strategies.
- Bofei Wang
- , Patrick K. Reville
- & Hussein A. Abbas
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Article
| Open AccessMolecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting
PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.
- Yasuo Kubota
- , Xiaorong Gu
- & Jaroslaw P. Maciejewski
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Article
| Open AccessCellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia
The cellular hierarchies in acute promyelocytic leukemia (APL) remain to be explored. Here, the authors perform single-cell RNA sequencing of 16 APL patients to characterise its cellular composition and develop an APL-specific stemness score for assessing the risk of early death in APL.
- Wen Jin
- , Yuting Dai
- & Kankan Wang
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Article
| Open AccessCell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing
Cell softness protects cytotoxic T lymphocytes (CTL) from autolysis by own soluble factors such as perforin secreted for killing target cells. Here the authors show that softness can be induced by YAP activation, and that T leukemic cells are more sensitive to YAP inhibition than CTLs, thereby hinting YAP inhibitors as a potential therapy for T leukemia.
- Yabo Zhou
- , Dianheng Wang
- & Bo Huang
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Article
| Open AccessLeukemic stem cells activate lineage inappropriate signalling pathways to promote their growth
In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.
- Sophie G. Kellaway
- , Sandeep Potluri
- & Constanze Bonifer
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| Open AccessLeukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche
The function of macrophages in myeloid leukaemia can be difficult to assess because of lack of differentiation between transformed and non-transformed cells. Here the authors use a chimeric mouse model to characterise the effect of myeloid leukaemia on bystander macrophages noting altered functional properties of these cells.
- Amy Dawson
- , Martha M. Zarou
- & G. Vignir Helgason
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Article
| Open AccessMutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia
The subset of chronic lymphocytic leukemia (CLL) expressing the IGLV3- 21R110 BCR light chain often shows an aggressive clinical course. Here the authors report the development and characterization of IGLV3-21R110- targeted CAR T cells, showing selective targeting and eradication of IGLV3- 21R110 expressing CLL cells.
- Florian Märkl
- , Christoph Schultheiß
- & Mascha Binder
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Article
| Open AccessTargeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) represents a high-risk B-ALL subtype. Here the authors report that Th17 cells and IL-17A expression are elevated in Ph+ B-ALL patients and that targeting IL-17A enhances imatinib efficacy in preclinical models.
- Feng Wang
- , Yunxuan Li
- & Bing Cui
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Article
| Open AccessTMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells
The immune receptor Transmembrane and immunoglobulin domain containing 2 (TMIGD2) mediates T-cell and nature killer cells co-stimulation upon B7-family HHLA2 engagement. Here, the authors show that TMIGD2 is expressed in Acute Myeloid Leukaemia stem cells regulating self-renewal and differentiation to facilitate leukemogenesis.
- Hao Wang
- , R. Alejandro Sica
- & Xingxing Zang
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Article
| Open AccessIntegrative genotyping of cancer and immune phenotypes by long-read sequencing
Single-cell transcriptomics excel in cell subset classification and can be augmented by suitable genotype information. Here the authors devise a long-read sequencing workflow, termed nanoranger, for detection of molecular barcodes from single-cell cDNA and apply this to clonal tracking of acute myeloid leukemia and identification of complex immune phenotypes.
- Livius Penter
- , Mehdi Borji
- & Catherine J. Wu
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Article
| Open AccessClonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells
The expansion of cells with TET2 mutations within the blood is associated with increased risk for all-cause mortality, development of leukemia and cardiovascular disease. Here authors show IL1 promotes the clonal expansion TET2 knockout cells, enhancing their self-renewal, promoting their myeloid bias and impairing an IL1 driven loss of methylation at lymphoid and erythroid regulatory elements.
- J. McClatchy
- , R. Strogantsev
- & A. Agarwal
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Article
| Open AccessLeukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening
CAR-T therapy is a promising treatment modality for B-cell malignancies, yet many patients relapse. Using an in vivo genomewide screen in a model of B cell leukemia, we identify an unexpected mechanism of CAR-T resistance in which interferon gamma from the in vivo tumor microenvironment induces an adaptive T-cell resistance program in tumor cells.
- Azucena Ramos
- , Catherine E. Koch
- & Michael T. Hemann
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Article
| Open AccessSystematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens
The role of HOXA9 in binding to noncoding regulatory sequences and regulates the downstream genes in MLL gene rearrangements (MLL-r) leukemia. Here, the use of CRISPR-mediated loss-of-function screen against HOXA9-bound peaks and integrative approaches reveal the noncoding regulation mechanism of HOXA9.
- Shaela Wright
- , Xujie Zhao
- & Chunliang Li
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Article
| Open AccessTargetable lesions and proteomes predict therapy sensitivity through disease evolution in pediatric acute lymphoblastic leukemia
The role of clonal evolution on the actionable proteome and response to therapy in childhood acute lymphoblastic leukemia (ALL) remains unknown. Here, targeted sequencing and proteomic analysis of paired ALL diagnosis and relapsed samples revealed PARP1 as a potential therapeutic target.
- Amanda C. Lorentzian
- , Jenna Rever
- & Philipp F. Lange
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Article
| Open AccessMinimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL
While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. Here, the authors investigate it using a next generation sequencing approach.
- Haipin Chen
- , Miner Gu
- & Xiaojun Xu
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Article
| Open AccessHomodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open AccessChromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia
The molecular mechanisms underlying relapse in pediatric B-lineage acute lymphoblastic leukemia (B-ALL) patients remain to be explored. Here, the authors characterise the chromatin accessibility landscape of B-ALL and identify subtype and drug response specific patterns.
- Han Wang
- , Huiying Sun
- & Yu Liu
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Article
| Open AccessIntegrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia
Tumor-associated myeloid cells directly support progression of T-cell acute lymphoblastic leukemia (TALL). Here, the authors show that T-ALL cells must contact myeloid cells and activate integrin signaling and downstream FAK/PYK2 kinases to survive.
- Aram Lyu
- , Ryan S. Humphrey
- & Lauren I. R. Ehrlich
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Article
| Open AccessSingle-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia
Single-cell RNA-seq could help identify acute myeloid leukaemia (AML) patients at high risk of relapse after therapy. Here, the authors use single-cell RNA-seq from paediatric AML samples to construct a 7-gene signature that can identify malignant cells at diagnosis, which are distinctly associated with relapse or complete remission.
- Hope Mumme
- , Beena E. Thomas
- & Manoj Bhasin
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Article
| 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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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 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 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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Article
| 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 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 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 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 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 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 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