Featured
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| Open AccessTRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation
c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.
- Ke Li
- , Feng Wang
- & Zhuo-wei Hu
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Article
| Open AccessSmall 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 AccessTumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma
The tumour microenvironment (TME) has a major role in chemoresistance in multiple myeloma. The authors show that a nanoparticle targeted to TME and loaded with bortezomib (BTZ) and Y27632 is more effective than free drugs, non-targeted and single-agent controls and reduces BTZ-related side effects.
- Cinzia Federico
- , Kinan Alhallak
- & Abdel Kareem Azab
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| Open AccessA stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia
Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells.
- Kyle Spinler
- , Jeevisha Bajaj
- & Tannishtha Reya
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Article
| Open AccessA deep learning diagnostic platform for diffuse large B-cell lymphoma with high accuracy across multiple hospitals
Replacing diagnostic histopathology with AI-based tools requires large training datasets and robustness to sample variability. Here, the authors present a deep learning platform with high accuracy in large diffuse B-cell lymphoma diagnosis across multiple hospitals, trained on small datasets.
- Dongguang Li
- , Jacob R. Bledsoe
- & Shaoguang Li
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Article
| Open AccessETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine
ETNK1 mutations are recurrent in leukemia but how they contribute to oncogenesis is still unclear. Here, the authors show that ETNK1 mutations increase mitochondrial activity, ROS and H2AX levels and that these effects can be rescued upon phosphoethanolamine supplementation.
- Diletta Fontana
- , Mario Mauri
- & Rocco Piazza
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Article
| Open AccessInfluence 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 AccessEnhanced 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 AccessXPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature
Xeroderma Pigmentosum group C (XP-C) is a rare genetic disorder characterised by deficient DNA repair leading to skin and internal cancer, but the latter is not well understood molecularly. Here the authors sequence genomes of non-skin cancers from XP-C patients to unravel its mutational patterns.
- Andrey A. Yurchenko
- , Ismael Padioleau
- & Sergey Nikolaev
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Article
| Open AccessTargeting N-myristoylation for therapy of B-cell lymphomas
N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.
- Erwan Beauchamp
- , Megan C. Yap
- & Luc G. Berthiaume
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Article
| Open AccessClonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.
- Kiyomi Morita
- , Feng Wang
- & Koichi Takahashi
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Article
| Open AccessCalreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN
Calreticulin del52 and ins5 mutations induce two phenotypically distinct myeloproliferative neoplasms in patients. Here the authors show that modeling these mutations in knock-in mice recapitulate the two diseases and highlight how they impact the different hematopoietic compartments.
- Camélia Benlabiod
- , Maira da Costa Cacemiro
- & Caroline Marty
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Article
| Open AccessT cell exhaustion and a failure in antigen presentation drive resistance to the graft-versus-leukemia effect
In hematopoietic stem cell transplants, T cells mediate graft-versus-leukemia (GVL), but GVL can fail leading to leukemia relapse. Here the authors use a mouse model in which T cells target the minor histocompatibility antigen H60 to show how this can occur, characterize the CD8+ T cell response and demonstrate how anti-CD40 antibody therapy improves GVL.
- Meng Zhou
- , Faruk Sacirbegovic
- & Warren D. Shlomchik
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Article
| Open AccessChlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V
Receptor tyrosine kinase mutations are frequent and associated with poor prognosis in acute myeloid leukemia (AML). Here the authors show that the antipsychotic drug chlorpromazine reduces AML cells viability by perturbing the intracellular localization of FLT3-ITD and KIT-D816V.
- Shinya Rai
- , Hirokazu Tanaka
- & Itaru Matsumura
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Article
| Open AccessAutophagy regulates fatty acid availability for oxidative phosphorylation through mitochondria-endoplasmic reticulum contact sites
How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML.
- Claudie Bosc
- , Nicolas Broin
- & Carine Joffre
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Article
| Open AccessH3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients
Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.
- Kolja Schleich
- , Julia Kase
- & Clemens A. Schmitt
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Article
| Open AccessAccelerated single cell seeding in relapsed multiple myeloma
In multiple myeloma, disease progresses via seeding to different anatomic sites and clonal expansion. Here, utilising autopsy material, the authors show that systemic seeding accelerates at relapse following treatment.
- Heather J. Landau
- , Venkata Yellapantula
- & Francesco Maura
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Article
| Open AccessEndogenous retroviruses are a source of enhancers with oncogenic potential in acute myeloid leukaemia
Transposable elements are a potential source of transcriptional regulators, but how these sequences contribute to oncogenesis remains poorly understood. Here, the authors identify endogenous retroviruses (ERVs) with acute myeloid leukemia (AML)-associated enhancer chromatin signatures, and provide evidence that ERV activation provides an additional layer of gene regulation in AML.
- Özgen Deniz
- , Mamataz Ahmed
- & Miguel R. Branco
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Article
| Open AccessPRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis
The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.
- Slim Mzoughi
- , Jia Yi Fong
- & Ernesto Guccione
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Article
| Open AccessIgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms
Immunoglobulin (Ig) rearrangement and translocation information are usually obtained by targeted sequencing of the respective loci. Here, the authors present the IgCaller algorithm, which extracts Ig heavy and light chain genetic properties from short-read whole-genome sequencing results to provide a feasible alternative to direct sequencing.
- Ferran Nadeu
- , Rut Mas-de-les-Valls
- & Elías Campo
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Article
| Open AccessMechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation.
- Yi Zhang
- , Yiran Guo
- & Tatiana G. Kutateladze
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Article
| Open AccessHematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells in the majority of patients with leukemia but not during normal blood formation. Here, the authors report a mouse model with conditional Cdx2 expression showing de novo leukemic transformation, and use it to optimize treatment in high-risk AML.
- Therese Vu
- , Jasmin Straube
- & Steven W. Lane
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Article
| Open AccessClonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant
Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
- Tarek H. Mouhieddine
- , Adam S. Sperling
- & Irene M. Ghobrial
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Article
| Open AccessNuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia
Loss of function mutations of NSD1 occur in blood cancers. Here, the authors report that NSD1 loss blocks erythroid differentiation which leads to an erythroleukemia-like disease in mice by impairing GATA1-induced target gene activation.
- Katharina Leonards
- , Marwa Almosailleakh
- & Juerg Schwaller
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Article
| Open AccessMYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies
Oncogene addiction is considered as a cancer cell-autonomous phenomenon, but can also influence the host immune system. Here the authors show that MYC-driven lymphomagenesis is associated with a block in the maturation and effector functions of natural killer cells as a mechanism of tumor escape from immunosurveillance.
- Srividya Swaminathan
- , Aida S. Hansen
- & Dean W. Felsher
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Article
| Open AccessEvolution and structure of clinically relevant gene fusions in multiple myeloma
Multiple myeloma is characterised by frequent gene fusions. Here, the authors use data from the Multiple Myeloma Research Foundation CoMMpass Study to further investigate fusion genes in this disease and their clinical relevance.
- Steven M. Foltz
- , Qingsong Gao
- & Ravi Vij
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Article
| Open AccessMBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia
The alternative splicing regulator MBNL1 is overexpressed in MLL-rearranged leukaemia. Here, the authors show that MBNL1-mediated alternative splicing leads to a specific splicing profile in MLL-rearranged leukaemia and loss or inhibition of MBNL1 impairs leukaemia development in vitro and in vivo.
- Svetlana S. Itskovich
- , Arun Gurunathan
- & Lynn H. Lee
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Article
| Open AccessBtk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms
Constitutive Btk signaling drives several B-cell cancers. Here the authors demonstrate key allosteric intramolecular interactions between the SH2 domain and the kinase domain of Btk, and propose an alternative approach for inhibition of both wild-type and tyrosine kinase inhibitor-resistant Btk.
- Daniel P. Duarte
- , Allan J. Lamontanara
- & Oliver Hantschel
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Article
| Open AccessHyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells
The identification of mRNA targets for RNA binding proteins (RBP) in stem cells is difficult due to the limited number of available cells. Here, as a proof-of-principle, the authors adapt the HyperTRIBE method to find that an RBP, MSI2, has increased RNA binding in leukemic compared with normal stem cells for selective regulation of oncogenic genes.
- Diu T. T. Nguyen
- , Yuheng Lu
- & Michael G. Kharas
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Article
| Open AccessProteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma
The mechanisms of action of proteasome inhibitors (PI) in multiple myeloma (MM) treatment are not fully elucidated. Here, the authors use unbiased phosphoproteomics in PI-treated MM and show increased phosphorylation of splicing-associated proteins, ultimately revealing splicing interference as a mode of PI action as well as demonstrating the spliceosome as a specific therapeutic vulnerability in this disease.
- Hector H. Huang
- , Ian D. Ferguson
- & Arun P. Wiita
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Article
| Open AccessTiming the initiation of multiple myeloma
The initial mutational processes and how these lead to progression in multiple myeloma (MM) are unclear. Here, the authors identify mutational signatures that occur over time in a large cohort of MM patients and suggest features that may help in early diagnosis.
- Even H. Rustad
- , Venkata Yellapantula
- & Francesco Maura
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Article
| Open AccessOncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation
Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.
- Shaima’a Hamarsheh
- , Lena Osswald
- & Robert Zeiser
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Article
| Open AccessDissecting the early steps of MLL induced leukaemogenic transformation using a mouse model of AML
The oncogene MLL is frequently translocated in leukemia, resulting in oncogenic fusion proteins. Here, the authors report a temporally controlled mouse model of MLL-ENL driven leukemia AND identify therapeutic targets associated with early MLL-ENL driven leukaemogenesis.
- Silvia Basilico
- , Xiaonan Wang
- & Berthold Göttgens
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Article
| Open AccessChromatin accessibility promotes hematopoietic and leukemia stem cell activity
Chromatin accessibility is a key mediator of gene expression and mutations in chromatin modifiers are frequently seen in cancers. Here, the authors show that the chromatin accessibility regulator HMGN1 - which is frequently mutated by amplification in leukemias - acts by blocking myeloid differentiation.
- Lucia Cabal-Hierro
- , Peter van Galen
- & Andrew A. Lane
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Article
| Open AccessElectron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma
Venetoclax monotherapy is effective in 40% of t(11:14) positive multiple myeloma (MM). Here, the authors show that electron transport chain complex I (CI) and complex II (CII) activity predict MM sensitivity to venetoclax, and inhibition of CI with IACS-010759 or CII with TTFA increase sensitivity.
- Richa Bajpai
- , Aditi Sharma
- & Mala Shanmugam
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Article
| Open AccessThe complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions.
- Ana Rio-Machin
- , Tom Vulliamy
- & Inderjeet Dokal
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Article
| Open AccessFOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML
FOXM1 is a known transcription factor which promotes cell proliferation in cancer cells. Here, the authors show that FOXM1 is required for the maintenance of quiescence and self-renewal of leukemia stem cells in MLL-AF9-rearranged acute myeloid leukemia patient and mouse models.
- Yue Sheng
- , Chunjie Yu
- & Zhijian Qian
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Article
| Open AccessEndogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
The ATM kinase is a key regulator of the DNA damage response to double-strand breaks (DSBs) and its homozygous loss in patients predisposes to lymphoid malignancies. Here, the authors develop a Tdp2−/− Atm−/− double-deficient mouse model to uncover topoisomerase II-induced DSBs as significant drivers of the genomic rearrangements that underpin these tumours.
- Alejandro Álvarez-Quilón
- , José Terrón-Bautista
- & Felipe Cortés-Ledesma
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Article
| Open AccessCD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide
CD229 is expressed on the surface of multiple myeloma cells, as well as B and T lymphocytes. Here, the authors engineer CD229-specific CAR T cells and, using patient samples and mouse models, show that treatment with these cells reduces tumour burden and results in limited targeting of T cells.
- Sabarinath V. Radhakrishnan
- , Tim Luetkens
- & Djordje Atanackovic
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Article
| Open AccessA combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells
Epigenetic changes can drive drug resistance in cancer. Here, the authors show that in BET inhibitor resistant leukaemia cells, genome-wide enhancer remodelling drives therapeutic resistance and targeting enhancer plasticity may overcome this resistance.
- Lei Guo
- , Jia Li
- & Yun Huang
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Article
| Open AccessClonal competition within complex evolutionary hierarchies shapes AML over time
Clonal evolution and heterogeneity has strong implications for treatment response in acute myeloid leukemia. Here, the authors use patient derived in vivo modelling to highlight the complex clonal and evolutionary dynamics underpinning acute myeloid leukemia progression.
- Carl Sandén
- , Henrik Lilljebjörn
- & Thoas Fioretos
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Article
| Open AccessChromatin 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 AccessAnti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains
Chimeric antigen receptors (CAR) use antibody variable regions to activate anti-tumor immunity. Here the authors show that a mouse IgH/IgL variable region used in a clinical CAR induces host immune responses to possibly reduce therapy efficacy, but an IgH-only CAR T design achieves similar CAR T activity but is potentially less immunogenic.
- Norris Lam
- , Nathan D. Trinklein
- & James N. Kochenderfer
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Article
| Open AccessSingle-cell analysis based dissection of clonality in myelofibrosis
Myelofibrosis is a myeloproliferative neoplasm. Here, the authors show the clonal evolution of myelofibrosis during JAK inhibitor therapy, revealing how the treatment results in an increase in clonal complexity and a gain of RAS pathway mutations.
- Elena Mylonas
- , Kenichi Yoshida
- & Frederik Damm
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Article
| Open AccessMLL-AF9 initiates transformation from fast-proliferating myeloid progenitors
Not all mutated cells become malignant, suggesting additional requirements for transformation. Here, the authors track blood progenitors from normal to malignancy driven by MLL-AF9, revealing a subset of myeloid progenitors predisposed to transformation dependent on their normal cycling state.
- Xinyue Chen
- , Daniel B. Burkhardt
- & Shangqin Guo
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Article
| Open AccessTargeting of apoptosis gene loci by reprogramming factors leads to selective eradication of leukemia cells
Yamanaka factors can reprogram somatic and cancer cells into induced pluripotent stem cells. Here, the authors show that the induction of these factors in acute myeloid leukemia leads to apoptosis of leukemia cells in vivo, and this is through modulation of chromatin accessibility to apoptotic genes and accompanied by H3K9me3 dysregulation.
- Yajie Wang
- , Ting Lu
- & Tao Cheng
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Article
| Open AccessInfectious 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 AccessMyeloid lineage enhancers drive oncogene synergy in CEBPA/CSF3R mutant acute myeloid leukemia
Acute Myeloid Leukemia (AML) develops following multiple mutations of differing impact. Here, the authors show that activating mutations of CSF3R co-operate with loss-of-function mutations of CEBPA to promote AML development through an enhancer-dependent mechanism.
- Theodore P. Braun
- , Mariam Okhovat
- & Julia E. Maxson
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Article
| Open AccessInvariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes
Stepwise acquisition of mutations gives rise to myelodysplastic syndrome (MDS) in older adults. Here, the authors infer the clonal hierarchy of 1809 MDS patients, revealing insights into the evolution of dominant/secondary mutations and how these impact clinical phenotypes like leukemic progression and therapy response.
- Yasunobu Nagata
- , Hideki Makishima
- & Jaroslaw P. Maciejewski