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| 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 AccessInhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Cancer stem cells are thought to be largely resistant to treatment and can be responsible for tumour recurrence. Here, using renal cancer organoids, self-renewing sphere cultures and PDX from patients, the authors show that the proliferation of stem cells within organoids, PDX and spheres can be blocked by the concomitant inhibition of the NOTCH and WNT pathways.
- Annika Fendler
- , Daniel Bauer
- & Walter Birchmeier
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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 AccessHSP90A inhibition promotes anti-tumor immunity by reversing multi-modal resistance and stem-like property of immune-refractory tumors
Nanog can confer resistance to cancer immunotherapy by promoting AKT activity. Here, the authors demonstrate that HSP90A is a Nanog target that stabilizes the AKT coactivator TCL1, thereby activating AKT, and that HSP90A inhibition can enhance the anti-tumor efficacy of adoptive T cell transfer and checkpoint blockade.
- Kwon-Ho Song
- , Se Jin Oh
- & Tae Woo Kim
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Article
| Open AccessMUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer
MUC1-C is overexpressed in castration-resistant prostate cancer and neuroendocrine prostate cancer. Here, the authors show that MUC1-C drives lineage plasticity through MYC and BRN2, inducing neuroendocrine features and stemness in prostate cancer.
- Yota Yasumizu
- , Hasan Rajabi
- & Donald Kufe
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Article
| Open AccessArf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice
Cancer stem cells (CSC) have been shown as the origin for therapeutic resistance and patient relapse. Here, the authors show that targeting Arf1-mediated lipid metabolism in CSC induces cell death but also an immunogenic anti-cancer response.
- Guohao Wang
- , Junji Xu
- & Steven X. Hou
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Article
| Open AccessTRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription
Cancer stem cells contribute to breast cancer metastasis and recurrence. Here the authors show that TRIB3 enhances breast cancer stemness through interaction with AKT to promote FOXO1 stability, which then increases SOX2 activity.
- Jin-mei Yu
- , Wei Sun
- & Zhuo-Wei Hu
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Article
| Open AccessHeterogeneity and dynamics of active Kras-induced dysplastic lineages from mouse corpus stomach
How a precancerous form (dysplasia) becomes gastric cancer is unclear. Here, the authors assess the role of Kras activation in heterogenous dysplastic cells in murine stomach corpus organoids, identifying two dysplastic stem cell populations and show that MEK inhibition causes alterations in cell behavior.
- Jimin Min
- , Paige N. Vega
- & Eunyoung Choi
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Article
| Open AccessLineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection
The development of post-chemotherapy resistance is a significant issue in the management of AML. Here, Caiado et al. suggest that the issue might be circumvented via upfront combination with hypomethylating agents that shape the clonal dynamics and transcriptional landscape of relapsing AML
- Francisco Caiado
- , Diogo Maia-Silva
- & Bruno Silva-Santos
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Article
| Open AccessMicroenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling
In breast cancer, dormant cancer cells may develop into bone metastases. Here, the authors demonstrate that microenvironmental IL1β stimulates metastatic breast cancer cell colonisation in the bone via IL1β-NFKB/CREB-Wnt pathway activation and cancer stem cell colony formation
- Rachel Eyre
- , Denis G. Alférez
- & Robert B. Clarke
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Article
| Open AccessMutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness
The role of histone mutations in leukemogenesis remains largely unexplored. In this study of AML, the authors show that histone mutations are early events that drive a more aggressive phenotype.
- Meaghan Boileau
- , Margret Shirinian
- & Kolja Eppert
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Article
| Open AccessTSPAN8 promotes cancer cell stemness via activation of sonic Hedgehog signaling
Tetraspanin 8 (TSPAN8) has been implicated in a number of different tumours, but the underlying mechanisms remain unclear. Here, in breast cancer the authors highlight a role for TSPAN8 in promoting tumorigenesis through the activation of Hedgehog signalling.
- Rongxuan Zhu
- , Olivier Gires
- & Hongxia Wang
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Article
| Open AccessMEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
Wnt signaling is necessary for colorectal cancer tumorigenesis and stem cell maintenance. Here, the authors identify MEK1/2 inhibitors as potent activators of Wnt/β-catenin signalling and show that clinically approved MEK inhibitors inadvertently induce stem cell plasticity in colorectal cancer
- Tianzuo Zhan
- , Giulia Ambrosi
- & Michael Boutros
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Article
| Open AccessHydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells
Transcriptome analysis of circulating tumor cells (CTCs) provides insights into monitoring target therapeutics and underlying tumor metastasis. Here the authors present Hydro-Seq, a contamination-free high-throughput hydrodynamic scRNA-seq barcoding technique for rare CTCs.
- Yu-Heng Cheng
- , Yu-Chih Chen
- & Euisik Yoon
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Article
| Open AccessCollagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung
Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating these collagen III/CD167a-driven metastatic foci.
- Yu-Cheng Lee
- , Antonina V. Kurtova
- & Keith Syson Chan
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Article
| Open AccessStem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment
Cancer stem cells (CSCs) comprise a putative population that can drive growth and resistance. Here, in glioblastoma models the authors show that rather than being a distinct clonal entity, the CSC population represents a plastic state adoptable by most cancer cells via reversible state transitions induced by the microenvironment.
- Anne Dirkse
- , Anna Golebiewska
- & Simone P. Niclou
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Article
| Open AccessTargeting bivalency de-represses Indian Hedgehog and inhibits self-renewal of colorectal cancer-initiating cells
The presence of bivalent epigenetic active and repressive histone marks control lineage-specific differentiation in embryonic stem cells. Here, the authors reveal that bivalent marks repress the differentiation gene IHH in colorectal cancer-initiating cells, and can be targeted by EZH2 inhibition
- Evelyne Lima-Fernandes
- , Alex Murison
- & Catherine A. O’Brien
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Article
| Open AccessA highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies
Myelodyplastic hematopoietic stem cells (MDS HSC) have eluded in vivo modeling. Here the authors present a highly efficient MDS patient-derived xenotransplantation model in cytokine-humanized mice with replication of the donors’ genetic complexity and myeloid, erythroid, and megakaryocytic lineage dysplasia.
- Yuanbin Song
- , Anthony Rongvaux
- & Stephanie Halene
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Article
| Open AccessAge-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias
Acute myeloid leukaemia (AML) affects people of all ages. Here, the authors model AML in vivo and demonstrate that the age of the cell of origin impacts leukaemia development and the genetic signature where adult cells of origin give rise exclusively to AML and young cells of origin give rise to myeloid, lymphoid or mixed phenotype acute leukaemia.
- Shahzya Chaudhury
- , Caitríona O’Connor
- & Karen Keeshan
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Article
| Open AccessTumour-vasculature development via endothelial-to-mesenchymal transition after radiotherapy controls CD44v6+ cancer cell and macrophage polarization
Radiotherapy is the main treatment for most cancer, but it is unclear if targeting tumour vasculature can enhance tumour radiosensitivity. Here, the authors show that tumour endothelial-mesenchymal transition after radiotherapy leads to proliferation of radioresistant CSCs and tumour associated macrophages polarization.
- Seo-Hyun Choi
- , A-Ram Kim
- & Yoon-Jin Lee
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Article
| Open AccessH3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression
The effects of epigenetic regulators on different tumor cell populations can affect their potential as anticancer targets. In this study, the authors demonstrate that the histone methyltransferase G9a is a suppressor of lung tumor-propagating cells and tumor progression, acting through chromatin modification with MMP10 as one of its targets for metastasis regulation.
- S. P. Rowbotham
- , F. Li
- & C. F. Kim
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Article
| Open AccessAnalysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma
The intrinsic drivers of glioblastoma (GBM) migration are still poorly understood. Here the authors purify GBM stem cells (GSCs) from patients and profile chromatin accessibility in these cells, identifying TEAD1 as a regulator of migration in human glioblastoma.
- Jessica Tome-Garcia
- , Parsa Erfani
- & Nadejda M. Tsankova
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Article
| Open AccessConservation of epigenetic regulation by the MLL3/4 tumour suppressor in planarian pluripotent stem cells
The Mll3/4 histone methyltransferases can act as tumour suppressors in humans. Here, the authors identify three orthologs of mammalian MLL3/4 in the planarian Schmidtea mediterranea and show that knockdown causes outgrowths in regenerating animals, suggesting that the tumour suppressive function of these genes is deeply conserved.
- Yuliana Mihaylova
- , Prasad Abnave
- & A. Aziz Aboobaker
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Article
| Open AccessLinking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses
The functional significance of the observed heterogeneity of androgen receptor (AR) expression in prostate cancer is unknown. Here the authors show AR expression heterogeneity is associated with distinct castration/enzalutamide responses and identify BCL-2 as a potential therapeutic target in castration-resistant prostate cancer.
- Qiuhui Li
- , Qu Deng
- & Dean G. Tang
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Article
| Open AccessAp4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells
The c-MYC oncoprotein has many targets whose actions are not fully understood including TFAP4/AP4. Here, the authors show in a mouse model of inherited colorectal cancer that deletion of AP4 decreased the frequency of c-MYC-driven intestinal adenomas, and reveal Ap4 as a mediator of adenoma initiation and regulator of colonic and intestinal stem cell and Paneth cell homeostasis.
- Stephanie Jaeckel
- , Markus Kaller
- & Heiko Hermeking
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Article
| Open AccessInhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy
IRE1/XBP-1 activation has a major role in Triple negative breast cancer (TNBC). Here, the authors show that inhibition of IRE1’s RNase activity attenuates autocrine and paracrine signaling of pro-tumorigenic cytokines and synergizes with paclitaxel to confer potent anti-tumor effects in TNBC.
- Susan E. Logue
- , Eoghan P. McGrath
- & Afshin Samali
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Article
| Open AccessTargeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
Stromal cell recruitment, activation and crosstalk with cancer cells is poorly understood. Here, the authors demonstrate that cancer cell-derived Hedgehog ligand triggers stromal remodeling that in turn induces a cancer-stem-cell like, drug-resistant phenotype of nearby cancer cells while treatment with smoothened inhibitors reverses these phenotypes.
- Aurélie S. Cazet
- , Mun N. Hui
- & Alexander Swarbrick
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| Open AccessAssessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells
The International Stem Cell Initiative tests methods in a multisite study to detect pluripotency and teratoma formation (PluriTest, Embryoid Body and Teratoma methods) in human pluripotent stem cells. Here, the authors provide guidelines for their application: only the teratoma assay offers evidence of malignant potential.
- Thomas F. Allison
- , Peter W. Andrews
- & Shinya Yamanaka
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Article
| Open AccessTGF-β induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression
In pancreatic ductal adenocarcinoma, TGF-β/Activin induce epithelial-to-mesenchymal transition (EMT) and stemness. Here, the authors show that TGF-β induces pro-tumourigenic miR-100 and miR-125b, but blocks anti-tumourigenic let-7a maturation via LIN28B, regulating pathways to promote stemness, EMT and tumourigenesis.
- Silvia Ottaviani
- , Justin Stebbing
- & Leandro Castellano
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Article
| Open AccessThe basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
Gene fusions involving MLL and different partner genes define unique subgroups of acute myelogenous leukemia, but the mechanisms underlying specific subgroups are not fully clear. Here the authors elucidate the mechanisms of MLL-AF6 induced transformation, providing a distinct pathway that involves SHARP1 as a critical target.
- Akihiko Numata
- , Hui Si Kwok
- & Daniel G. Tenen
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Article
| Open AccessCx26 drives self-renewal in triple-negative breast cancer via interaction with NANOG and focal adhesion kinase
Connexin proteins are usually considered as tumor suppressors. Here, the authors show that connexin 26 (Cx26) regulates the self-renewal of breast cancer stem cells via a ternary complex with FAK and NANOG.
- Praveena S. Thiagarajan
- , Maksim Sinyuk
- & Justin D. Lathia
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Article
| Open AccessA non-cell-autonomous role for Pml in the maintenance of leukemia from the niche
Persistence of resistant leukemic cells after therapy is the main cause of relapse. Here, the authors show that mesenchymal stem cells-derived PML is involved in the maintenance of leukemia cells through Cxcl1 and IL6 and that PML inhibition enhances sensitivity to chemotherapy.
- Jlenia Guarnerio
- , Lourdes Maria Mendez
- & Pier Paolo Pandolfi
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Article
| Open AccessAlu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma
The treatment of multiple myeloma is challenging due to high relapse rates. Here the authors show that expression of ADAR1 correlates with poor patient outcomes, and that ADAR1-mediated editing of GLI1 is a mechanism relevant in the context of multiple myeloma progression and drug resistance.
- Elisa Lazzari
- , Phoebe K. Mondala
- & Catriona H. M. Jamieson
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Article
| Open AccessStem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma
Senescent cells can promote tumour progression through the activation of a senescenceassociated secretory phenotype (SASP). Here, the authors show that SASP activation is associated with non-cell autonomous cell transformation and tumour initiation in an in vivo model of adamantinomatous craniopharyngioma.
- Jose Mario Gonzalez-Meljem
- , Scott Haston
- & Juan Pedro Martinez-Barbera
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Article
| Open AccessThe combination of CHK1 inhibitor with G-CSF overrides cytarabine resistance in human acute myeloid leukemia
Overriding cytarabine resistance in AML remains an unmet medical need. Here, the authors show that the CHK1 inhibitor GDC-0575 in combination with cytarabine and G-CSF has a significant anti-leukemic effect without toxicity to normal marrow stem and progenitor cells.
- Alessandro Di Tullio
- , Kevin Rouault-Pierre
- & Dominique Bonnet
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Article
| Open Access3D collagen architecture induces a conserved migratory and transcriptional response linked to vasculogenic mimicry
Extracellular matrix plays a central role in driving cancer development. Here the authors using an in vitro approach show that confining collagen architectures induce fast and persistent cell migration and the formation of multicellular network structures linked to vascular mimicry observed in tumours from patients.
- D. O. Velez
- , B. Tsui
- & S. I. Fraley
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Article
| Open AccessRole of epithelial to mesenchymal transition associated genes in mammary gland regeneration and breast tumorigenesis
The contribution of EMT in mammary gland homeostasis and human breast cancer is still unclear. Here, using in vivo lineage tracing and breast cancer PDXs the authors demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in breast cancer is independent of expression of EMT-associated genes.
- Shaheen S. Sikandar
- , Angera H. Kuo
- & Michael F. Clarke
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Article
| Open AccessEvidence of renal angiomyolipoma neoplastic stem cells arising from renal epithelial cells
Renal angiomyolipomas (AML) contain a mix of clonal tumour cells. Here, through reverse tumour engineering experiments, mouse genetics and analyses of human AML tumours, the authors provide evidence that these mesenchymal tumours originate from renal proximal tubule epithelial cells.
- Ana Filipa Gonçalves
- , Mojca Adlesic
- & Ian J. Frew
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Article
| Open AccessMulticolor lineage tracing reveals clonal architecture and dynamics in colon cancer
The clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. Here, the authors describe the clonal architecture and dynamics in human colon cancer by using a multicolor lineage tracing approach in colon cancer xenografts.
- Sebastian Lamprecht
- , Eva Marina Schmidt
- & David Horst
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Article
| Open AccessCaMKII-mediated Beclin 1 phosphorylation regulates autophagy that promotes degradation of Id and neuroblastoma cell differentiation
Neuroblastoma cell differentiation is regulated by Id proteins. Here, the authors show that CaMKII-mediated phosphorylation of Beclin 1 can activate K63-linked ubiquitination and autophagic degradation of Id proteins uncovering a role for autophagy in cell differentiation.
- Xuan Li
- , Xiao-Qi Wu
- & Xiao-Feng Zhu
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Article
| Open AccessBCL-XL directly modulates RAS signalling to favour cancer cell stemness
BCL-XL provides a survival advantage to cancer cells even in the absence of apoptotic pressures. In this study, the authors show that BCL-XL interacts with RAS in a BH4-dependent manner and regulates RAS-mediated activation of pathways involved in the stemness feature of breast cancer cells.
- Sophie de Carné Trécesson
- , Frédérique Souazé
- & Philippe Paul Juin
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Article
| Open AccessA covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action
PIN1 is a promising therapeutic target for cancer treatment. In this study, the authors identify a covalent inhibitor of PIN1 with anti-tumour and anti-metastatic properties thanks to PIN1 inactivation and to the release, after binding to PIN1, of a quinone-mimicking compound that elicits reactive oxygen generation and causes DNA damage.
- Elena Campaner
- , Alessandra Rustighi
- & Giannino Del Sal
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Article
| Open AccessLoss of Asxl2 leads to myeloid malignancies in mice
ASXL2 mutations are mostly found in a subset of leukemia patients with certain genetic aberrations; however the role of this protein in normal hematopoiesis and related malignancies is still unclear. Here the authors use a knock-out mouse model to uncover the role of Asxl2in hematopoiesis and leukemogenesis.
- Jianping Li
- , Fuhong He
- & Feng-Chun Yang
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Article
| Open AccessTumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth
Tumour-associated macrophages (TAMs) facilitate malignant growth of glioblastoma (GBM). Here, the authors show that TAMs support glioma stem cell renewal via paracrine signalling to the pleiotrophin receptor PTPRZ1 and that blocking this axis results in increased survival of tumour-bearing animals.
- Yu Shi
- , Yi-Fang Ping
- & Xiu-Wu Bian
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Article
| Open AccessASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia
While the role of ASLX1 in haematopoiesis and leukaemia has been heavily studied, the role of ASLX2 is unclear. Here the authors show that ASLX2 is required for normal haematopoietic stem cell self-renewal whereas Asxl2 loss promotes leukemogenesis, thus explaining the frequently observed mutations in AML patients
- Jean-Baptiste Micol
- , Alessandro Pastore
- & Omar Abdel-Wahab
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Article
| Open AccessBlockade of IDO-kynurenine-AhR metabolic circuitry abrogates IFN-γ-induced immunologic dormancy of tumor-repopulating cells
Tumour repopulating cells (TRC) are stem-like cells that can escape immune-mediated killing. Here, the authors show IFN-γ results in either dormancy or apoptosis of TRC depending on the activation of the IDO1 metabolic pathway, and that combining IFN-γ with IDO1 inhibitors results in enhanced tumour regression.
- Yuying Liu
- , Xiaoyu Liang
- & Bo Huang
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Article
| Open AccessKDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling
Epigenetic factors can regulate functional properties of human colorectal cancer stem cells. Here, the authors show that histone demethylases of the KDM3 family activate Wnt signalling in colorectal cancer stem cells by erasing H3K9me2 marks on Wnt target genes and recruiting MLL1 to promote H3K4 methylation.
- Jiong Li
- , Bo Yu
- & Cun-Yu Wang
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Article
| Open AccessLkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2
The mechanisms that govern the transdifferentiation of lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) are not fully understood. Here, the authors show that EZH2 loss exacerbates the transdifferentiation of ADCs to SCCs as a result of chromatin changes that lead to expression of squamous differentiation genes.
- Haikuo Zhang
- , Christine Fillmore Brainson
- & Kwok-Kin Wong
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Article
| Open AccessInduced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours
Several breast cancers may originate from mammary luminal cells and inactivating mutations of p53 are present in most triple-negative breast cancers. Here, the authors show that loss of p53 from luminal cells in mice results in their clonal expansion and mammary tumour formation.
- Luwei Tao
- , Dongxi Xiang
- & Zhe Li