Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.

• Publication year

  2019

• Venue

  Klinische Pädiatrie

• Publication date

  2019-04-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.ccell.2019.03.004PMID 30991026PMCID PMC6541931
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• COSMIC: the Catalogue Of Somatic Mutations In Cancer

  2018cited by this paper
• Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia

  2018influential reference
• The PRIDE database and related tools and resources in 2019: improving support for quantification data

  2018influential reference
• Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response

  2018cited by this paper
• Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?

  2018cited by this paper
• Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia

  2018cited by this paper
• Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase.

  2018cited by this paper
• Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities

  2017cited by this paper
• The Ubiquitin Code in the Ubiquitin-Proteasome System and Autophagy.

  2017cited by this paper
• Decreased relapsed rate and treatment‐related mortality contribute to improved outcomes for pediatric acute myeloid leukemia in successive clinical trials

  2017cited by this paper
• Nonradioactive quantification of autophagic protein degradation with L-azidohomoalanine labeling

  2017cited by this paper
• Lgr5 Functions As Negative Regulator of Wnt Signaling in B Cells and Is Critical for Self-Renewal of Normal and Transformed B Cells

  2017cited by this paper
• The role of Wnt signaling in hematopoietic stem cell development

  2017cited by this paper
• Evaluation of off-target and on-target scoring algorithms and integration into the guide RNA selection tool CRISPOR

  2016cited by this paper
• The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

  2016cited by this paper
• MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells

  2016cited by this paper
• Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice.

  2016cited by this paper
• Wnt‐induced deubiquitination FoxM1 ensures nucleus β‐catenin transactivation

  2016cited by this paper
• Open-gate mutants of the mammalian proteasome show enhanced ubiquitin-conjugate degradation

  2016influential reference
• CrispRVariants charts the mutation spectrum of genome engineering experiments

  2016cited by this paper
• Caught in a Wnt storm: Complexities of Wnt signaling in hematopoiesis.

  2016cited by this paper
• Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration.

  2015influential reference
• Maternal Wnt/STOP signaling promotes cell division during early Xenopus embryogenesis

  2015cited by this paper
• MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens

  2014cited by this paper
• Mitotic wnt signaling promotes protein stabilization and regulates cell size.

  2014cited by this paper
• Improved vectors and genome-wide libraries for CRISPR screening

  2014cited by this paper
• Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia

  2014influential reference
• Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells

  2014cited by this paper
• Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities.

  2014cited by this paper
• Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation

  2013cited by this paper
• WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation.

  2013cited by this paper
• Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system.

  2013cited by this paper
• Optimizing asparaginase therapy for acute lymphoblastic leukemia

  2013cited by this paper
• Wnt signaling in normal and malignant hematopoiesis.

  2013cited by this paper
• Failure of Amino Acid Homeostasis Causes Cell Death following Proteasome Inhibition

  2012cited by this paper
• The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity

  2012cited by this paper
• Slug and Sox9 cooperatively determine the mammary stem cell state.

  2012cited by this paper
• Low expression of asparagine synthetase in lymphoid blasts precludes its role in sensitivity to L-asparaginase.

  2012cited by this paper
• The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia.

  2012cited by this paper
• Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study.

  2011cited by this paper
• Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling

  2011cited by this paper
• The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation

  2011influential reference
• LGR5 Is a Negative Regulator of Tumourigenicity, Antagonizes Wnt Signalling and Regulates Cell Adhesion in Colorectal Cancer Cell Lines

  2011cited by this paper
• Safe harbours for the integration of new DNA in the human genome

  2011cited by this paper
• Lentiviral Vectors to Probe and Manipulate the Wnt Signaling Pathway

  2010cited by this paper
• Wnt signaling requires sequestration of glycogen synthase kinase 3 inside multivesicular endosomes.

  2010cited by this paper
• Functional redundancy of GSK-3alpha and GSK-3beta in Wnt/beta-catenin signaling shown by using an allelic series of embryonic stem cell lines.

  2007cited by this paper
• The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia

  2007cited by this paper
• Crystal structure and allosteric regulation of the cytoplasmic Escherichia coli L-asparaginase I.

  2007cited by this paper
• FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors

  2007cited by this paper
• Functional redundancy of GSK-3α and GSK-3β in wnt/β-catenin signaling shown by using an allelic series of embryonic stem cell lines

  2007cited by this paper
• Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia.

  2006cited by this paper
• TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.

  2006cited by this paper
• Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

  2005cited by this paper
• Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia.

  2005influential reference
• Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

  2005cited by this paper
• Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment.

  2004cited by this paper
• The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation

  2004cited by this paper
• Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL.

  2003cited by this paper
• Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation.

  2003cited by this paper
• Vertebrate proteins related to Drosophila Naked Cuticle bind Dishevelled and antagonize Wnt signaling.

  2001cited by this paper
• Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCFFbw7 Ubiquitin Ligase

  2001cited by this paper
• The APC tumor suppressor protein in development and cancer.

  1997influential reference
• Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF.

  1997cited by this paper
• Integrating genetic approaches into the discovery of anticancer drugs.

  1997cited by this paper
• pangolinencodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila

  1997cited by this paper
• Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels.

  1996influential reference
• An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database

  1994cited by this paper
• Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: a report from the Childrens Cancer Group.

  1993cited by this paper
• wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate.

  1992cited by this paper
• The N-terminal cysteine of human asparagine synthetase is essential for glutamine-dependent activity.

  1989cited by this paper
• Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia--a Cancer and Leukemia Group B Study.

  1988cited by this paper
• Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia.

  1986influential reference
• Effective dose of L-asparaginase for induction of remission in previously treated children with acute lymphocytic leukemia: a report from Childrens Cancer Study Group.

  1979influential reference
• l-asparaginase resistance in human leukemia--asparagine synthetase.

  1969cited by this paper
• Asparagine Synthetase Activity of Mouse Leukemias

  1968cited by this paper
• EVIDENCE THAT THE L-ASPARAGINASE OF GUINEA PIG SERUM IS RESPONSIBLE FOR ITS ANTILYMPHOMA EFFECTS

  1963cited by this paper
• Evidence that the L-Asparaginase Activity of Guinea Pig Serum is responsible for its Antilymphoma Effects

  1961cited by this paper

• Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas.

  2026cites this paper
• Mechanistic insights into L-asparaginase resistance in cancers.

  2025cites this paper
• Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply

  2025cites this paper
• The interplay between Wnt and mTOR signaling modulates ciliogenesis in human retinal epithelial cells

  2025cites this paper
• Wnt10b signaling regulates replication stress–induced chromosomal instability in human cancer

  2025cites this paper
• Underlying biology, challenges and emergent concepts in the treatment of relapsed and refractory pediatric T-cell acute lymphoblastic leukemia

  2025cites this paper
• The ASNS inhibitor ASX-173 potentiates L-asparaginase anticancer activity

  2025cites this paper
• GSK3α negatively regulates GSK3β by decreasing its protein levels and enzymatic activity in mouse embryonic stem cells

  2025cites this paper
• Perspectives on cancer therapy—synthetic lethal precision medicine strategies, molecular mechanisms, therapeutic targets and current technical challenges

  2025cites this paper
• SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response

  2025cites this paper
• A methyltransferase-independent role for METTL1 in tRNA aminoacylation and oncogenic transformation.

  2025cites this paper
• Targeting Asparagine Metabolism in Solid Tumors

  2025cites this paper
• Metabolism of asparagine in the physiological state and cancer

  2024cites this paper
• A human-like glutaminase-free asparaginase is highly efficacious in ASNSlow leukemia and solid cancer mouse xenograft models.

  2024cites this paper
• Cancer Therapies Targeting Cellular Metabolism.

  2024cites this paper
• Post-translational modifications in drug resistance.

  2024cites this paper
• Emerging roles of small extracellular vesicles in metabolic reprogramming and drug resistance in cancers

  2024cites this paper
• l‐Asparaginase Bio‐Betters: Insight Into Current Formulations, Optimization Strategies and Future Bioengineering Frontiers in Anti‐Cancer Drug Development

  2024cites this paper
• Asparagine: a key metabolic junction in targeted tumor therapy.

  2024cites this paper
• Asparagine transport through SLC1A5/ASCT2 and SLC38A5/SNAT5 is essential for BCP‐ALL cell survival and a potential therapeutic target

  2024cites this paper
• Cilia as Wnt signaling organelles.

  2024cites this paper
• A novel GSK3β inhibitor 5n attenuates acute kidney injury

  2024cites this paper
• Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia

  2024cites this paper
• The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

  2024cites this paper
• Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

  2024cites this paper
• Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia

  2023cites this paper
• Biochemical Markers of Tumor Cell Sensitivity to L-Asparaginase

  2023cites this paper
• Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity

  2023cites this paper
• GSK3 as a Master Regulator of Cellular Processes

  2023cites this paper
• A review of Glycogen Synthase Kinase-3 (GSK3) inhibitors for cancers therapies.

  2023cites this paper
• GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

  2023cites this paper
• P327: LOSS OF POLYCOMB REPRESSIVE COMPLEX 2 FUNCTION CAUSES ASPARAGINASE RESISTANCE IN T-ACUTE LYMPHOBLASTIC LEUKAEMIA THROUGH DECREASED WNT PATHWAY ACTIVITY

  2023influential citation
• Genome-Wide CRISPR Screening for the Identification of Therapy Resistance-Associated Genes in Urothelial Carcinoma.

  2023cites this paper
• Application of CRISPR screen in mechanistic studies of tumor development, tumor drug resistance, and tumor immunotherapy

  2023cites this paper
• Multimodal Wnt signalling in the mouse neocortex.

  2023cites this paper
• Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis.

  2023cites this paper
• Targeting SHP2 phosphatase in hematological malignancies

  2022cites this paper
• Amino Acid Metabolism in Cancer Drug Resistance

  2022cites this paper
• Genome-wide screens identify specific drivers of mutant hTERT promoters

  2022cites this paper
• High-throughput methods for genome editing: the more the better.

  2022cites this paper
• Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

  2022cites this paper
• Mechanisms of Development of Side Effects and Drug Resistance to Asparaginase and Ways to Overcome Them

  2022cites this paper
• Metabolism and Endocrine Disorders: What Wnt Wrong?

  2022cites this paper
• Amino acid metabolism: challenges and opportunities for the therapeutic treatment of leukemia and lymphoma

  2022cites this paper
• Wnt signalling in cell division: from mechanisms to tissue engineering.

  2022cites this paper
• Identification of an Epi-metabolic dependency on EHMT2/G9a in T-cell acute lymphoblastic leukemia

  2022cites this paper
• Supramolecular assembly of GSK3α as a cellular response to amino acid starvation.

  2022cites this paper
• Tumoral microenvironment prevents de novo asparagine biosynthesis in B cell lymphoma, regardless of ASNS expression

  2022cites this paper
• Primary Cilia are WNT Transducing Organelles whose Biogenesis is Regulated by a WNT┫ PP1 axis

  2022cites this paper
• Clustered regularly interspaced short palindromic repeats screens in pediatric tumours: A review

  2022cites this paper
• Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets.

  2022cites this paper
• Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

  2021cites this paper
• Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia

  2021cites this paper
• Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex

  2021cites this paper
• Targeting leukemia-specific dependence on the de novo purine synthesis pathway

  2021cites this paper
• Wnt signaling activation: targets and therapeutic opportunities for stem cell therapy and regenerative medicine

  2021cites this paper
• Asparagine: A Metabolite to Be Targeted in Cancers

  2021cites this paper
• FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration

  2021cites this paper
• CRISPR screen in cancer: status quo and future perspectives.

  2021cites this paper
• E3 Ubiquitin Ligase in Anticancer Drugdsla Resistance: Recent Advances and Future Potential

  2021cites this paper
• Tilting MYC toward cancer cell death.

  2021cites this paper
• WNT as a Driver and Dependency in Cancer.

  2021cites this paper
• To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases

  2021cites this paper
• CRISPR Screens in Synthetic Lethality and Combinatorial Therapies for Cancer

  2021cites this paper
• GSK-3: a multifaceted player in acute leukemias

  2021cites this paper
• Amino Acid Depletion Therapies: Starving Cancer Cells to Death.

  2021cites this paper
• Multi-omics characterization of WNT pathway reactivation to ameliorate BET inhibitor resistance in liver cancer cells.

  2021cites this paper
• Re-defining synthetic lethality by phenotypic profiling for precision oncology.

  2021cites this paper
• The multiple ways Wnt signaling contributes to acute leukemia pathogenesis

  2020cites this paper
• Potential of CRISPR screen in target discovery for cancer immunotherapy.

  2020cites this paper
• Endothelial Cells (ECs) Metabolism: A Valuable Piece to Disentangle Cancer Biology.

  2020cites this paper
• A novel artificial intelligence protocol for finding potential inhibitors of acute myeloid leukemia.

  2020cites this paper
• Supercharging BRD4 with NUT in carcinoma

  2020cites this paper
• Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis

  2020cites this paper
• Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer

  2020influential citation
• Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy.

  2020influential citation
• Free Asparagine or Die: Cancer Cells Require Proteasomal Protein Breakdown to Survive Asparagine Depletion.

  2020cites this paper
• A Gene Expression High-Throughput Screen (GE-HTS) for Coordinated Detection of Functionally Similar Effectors in Cancer

  2020cites this paper
• Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells

  2020cites this paper
• The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas

  2020cites this paper
• Improving the Treatment of Acute Lymphoblastic Leukemia

  2020cites this paper
• Functional and structural evaluation of the antileukaemic enzyme l-asparaginase II expressed at low temperature by different Escherichia coli strains

  2020cites this paper
• Genetic biomarkers of drug resistance: A compass of prognosis and targeted therapy in acute myeloid leukemia.

  2020cites this paper
• Metabolic dependencies and vulnerabilities in leukemia

  2019cites this paper
• SLC1A3 contributes to L‐asparaginase resistance in solid tumors

  2019influential citation
• The conditional nature of gene essentiality.

  2019cites this paper
• Why imaging data alone is not enough: AI-based integration of imaging, omics, and clinical data

  2019cites this paper
• Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles

  2019cites this paper
• Targeting extracellular nutrient dependencies of cancer cells

  2019cites this paper
• Targeting metabolic dependencies in pediatric cancer.

  2019cites this paper
• CRISPR-Cas9-mediated loss-of-function screens

  2019cites this paper