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Article
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Cell 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 Access
Targeting 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 Access
Leukemia-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
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Systematic 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 Access
Minimal 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 Access
Chromatin 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 Access
Integrin 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 Access
Immune 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 Access
From 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 Access
Clonal 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 Access
Proteasome 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
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Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability
The ETV6-RUNX1 chimeric- and native RUNX1-responsive regulomes in paediatric B-acute lymphoblastic leukemia (B-ALL) remain to be characterized. Here, the authors reveal functional antagonism between the two transcription factors predominantly for the regulation of cell cycle-associated pathways and dependency on native RUNX1 for tumorigenesis which can be targeted pharmacologically.
- Jason P. Wray
- , Elitza M. Deltcheva
- & Tariq Enver
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Article
| Open Access
DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia
The role of DNA methylation in predisposing to pediatric acute lymphoblastic leukemia remains unknown. Here, the authors utilize a discordant twin model to investigate how DNA methylation variation contributes to disease risk in genetically identical subjects.
- Eric M. Nickels
- , Shaobo Li
- & Joseph L. Wiemels
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Article
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Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia
Different molecular subtypes defined by specific gene rearrangements have been described for acute lymphoblastic leukaemia (ALL). Here, the authors show that ZNF384 fusion activates FLT3 expression conferring a therapeutic vulnerability for ZNF384- rearranged ALL subtype.
- Xujie Zhao
- , Ping Wang
- & Jun J. Yang
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Article
| Open Access
CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies
The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.
- Yongxian Hu
- , Jingjing Li
- & He Huang
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Article
| Open Access
Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia
The molecular heterogeneity of KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) remains poorly characterised. Here, the authors perform multi-omics analysis for 84 ALL patients and suggest 5 distinct subgroups for risk stratification and personalised treatment.’
- Tomoya Isobe
- , Masatoshi Takagi
- & Junko Takita
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Article
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Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing
Host versus graft reaction is a major impediment to CAR-T cell immune therapy in allogeneic settings. Authors show here that CAR-T cells, engineered to be deficient in MHC I expression but to express the NK inhibitor HLA-E, are resistant to destruction by both T and NK cells of the host.
- Sumin Jo
- , Shipra Das
- & Julien Valton
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Article
| Open Access
Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis
Ph+ and Ph-like B-ALL remain poor prognosis leukemias. VAV3, a guanine nucleotide exchange factor, is activated and overexpressed in these leukemias. Here the authors reveal that leukemic VAV3 is predominantly nuclear. Nuclear VAV3, through its guanine nucleotide exchange factor and its effector nuclear RAC2, controls the repressive transcriptional activity of the polycomb repression complex-1 via nuclear AKT/PHLPP2 regulated BMI1.
- R. C. Nayak
- , K. H. Chang
- & J. A. Cancelas
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Article
| Open Access
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia
Notch1 is frequently activated promoting T-cell acute lymphoblastic leukaemia (T-ALL). Here, the authors show that Notch1 induces oxidative phosphorylation dependency in T-ALL and synergism when inhibiting both mitochondrial complex I and glutaminolysis in preclinical murine and human xenograft models.
- Natalia Baran
- , Alessia Lodi
- & Marina Konopleva
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Article
| Open Access
Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. Here the authors characterize the anti-tumor activity of allogeneic anti-CD123 CAR-T cells in preclinical models of BPDCN.
- Tianyu Cai
- , Agnès Gouble
- & Marina Konopleva
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Article
| Open Access
Integrative 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
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Article
| Open Access
Distinct 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
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Article
| Open Access
Obesity-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
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Article
| Open Access
Phosphoproteomic 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
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Article
| Open Access
CytofIn 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
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Article
| Open Access
An 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
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Article
| Open Access
Interleukin-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
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Article
| Open Access
Quinacrine-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
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Article
| Open Access
Single-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
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Article
| Open Access
A 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
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Article
| Open Access
Deciphering 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
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Article
| Open Access
Adipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence
How the bone marrow microenvironment evolves during induction chemotherapy to facilitate acute lymphoblastic leukaemia (ALL) survival remains unclear. Here the authors show that adipocytes emergent during ALL therapy aid the survival of ALL cells through a restrictive effect on the ALL proteome.
- Q. Heydt
- , C. Xintaropoulou
- & B. Patel
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Article
| Open Access
Oncogenic 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
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Article
| Open Access
3D 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
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Article
| Open Access
Proteomics 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
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Article
| Open Access
Single-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
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Article
| Open Access
Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells
The tumour microenvironment provides signals to support leukaemic stem cells (LSC) maintenance and chemoresistance. Here, the authors show that disrupting niche-associated signalling by inhibiting receptor-mediated endocytosis with a dynamin GTPase inhibitor overcomes chemoresistance of LSC.
- Cedric S. Tremblay
- , Sung Kai Chiu
- & David J. Curtis
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Article
| Open Access
Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia
CAR T therapy has some efficacy in the treatment of patients with refractory/relapsed B-cell acute lymphoblastic leukemia; however in some patients further relapse is encountered. Here, the authors conduct a Phase II clinical trial of a CD19 CAR T and demonstrate that patients with extramedullary disease are more likely to relapse than those without.
- Furun An
- , Huiping Wang
- & Zhimin Zhai
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Article
| Open Access
Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9
Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells.
- Lintao Liu
- , Enguang Bi
- & Qing Yi
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Article
| Open Access
Infectious stimuli promote malignant B-cell acute lymphoblastic leukemia in the absence of AID
Infection or chronic inflammation is a risk factor for childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors show that the DNA editing enzyme AID is expressed in infected B cells but using genetic mouse models show that it does not contribute to leukemia pathogenesis.
- Guillermo Rodríguez-Hernández
- , Friederike V. Opitz
- & Arndt Borkhardt
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Article
| Open Access
Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk
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
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Article
| Open Access
Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia
Studies with patient derived xenografts are hampered by factors such as genetic variability and sample availability. Here, the authors generate a leukemia mouse model by lentiviral transduction of normal human cord blood and show an oncogenic role of HOXB genes.
- Manabu Kusakabe
- , Ann Chong Sun
- & Andrew P. Weng
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Article
| Open Access
Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia
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
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Article
| Open Access
The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors
The upstream pathways regulating leukemic transcriptional plasticity for differentiation arrest and resistance to therapy are unclear. Here the authors show that aPKC λ/ι-controls leukemic B-cell precursor differentiation arrest trough RAC/MEK/ERK/SATB2 epigenetic repression
- R. C. Nayak
- , S. Hegde
- & J. A. Cancelas
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Article
| Open Access
ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways
Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia.
- Thuc M. Le
- , Soumya Poddar
- & Caius G. Radu
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Article
| Open Access
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
- Zhaohui Gu
- , Michelle Churchman
- & Charles G. Mullighan
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Article
| Open Access
ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival
Lymphocytic leukaemia cells are characterized by high respiratory rates. Here, the authors report that the oxysterol-binding protein ORPL4 sustains mitochondrial respiration in T-cell acute lymphoblastic leukaemia cells by regulating Ca2+release from the endoplasmic reticulum.
- Wenbin Zhong
- , Qing Yi
- & Daoguang Yan
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Article
| Open Access
CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
CAR-T targeting CD19 have been successfully used in a variety of B-cell malignancies but patients may eventually relapse. Here, the authors show that CD19 CAR-T resistance in pre-B cell ALL can be due to the induction of a myeloid lineage switch through an epigenetic alterations in master regulators of B cell development.
- Elad Jacoby
- , Sang M. Nguyen
- & Terry J. Fry
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Article
| Open Access
A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development
NFATc1 orchestrates thymocyte development. Here the authors show that NFATc1 expression is regulated by distinct promoters during thymocyte differentiation, and by conditional deletion of individual promoters in mice they define their specific roles in the control of T-cell development by NFATc1.
- Stefan Klein-Hessling
- , Ronald Rudolf
- & Amiya Kumar Patra
Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment