Evidence map›Paper›PMID 30991026›Full record

ArticleCancer cell2019

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

Laura Hinze, Maren Pfirrmann, Salmaan Karim, James Degar, Connor McGuckin, Divya Vinjamur, Joshua Sacher, Kristen E Stevenson, Donna S Neuberg, Esteban Orellana and 6 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.

0numbers the graph read from it
0cells of the map it votes in
59citing papers in PubMed
10.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

59 citing papers in PubMed, 104 citations in OpenAlex.

  1. Article
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  15. Metabolism of asparagine in the physiological state and cancer.Cell communication and signaling : CCS · 2024
    Review
  16. Review
  17. Amino acid metabolism reprogramming: shedding new light on T cell anti-tumor immunity.Journal of experimental & clinical cancer research : CR · 2023
    Review
  18. GSK3 as a Master Regulator of Cellular Processes.International journal of molecular sciences · 2023
    Article
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors at 4 institutions in 2 countries.

Laura HinzeDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.
Maren PfirrmannDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Salmaan KarimDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
James DegarDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Connor McGuckinDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Divya VinjamurDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
Joshua SacherStanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Kristen E StevensonDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02445, USA.
Donna S NeubergDepartment of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02445, USA.
Esteban OrellanaDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Martin StanullaDepartment of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.
Richard I GregoryDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Daniel E BauerDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA.
Florence F WagnerStanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Kimberly StegmaierDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Alejandro GutierrezDivision of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: alejandro.gutierrez@childrens.harvard.edu.
Boston Children's Hospital · USBroad Institute · USDana-Farber Cancer Institute · USMedizinische Hochschule Hannover · DE

Funding

Integrating Transforming Approaches to Identify and Target New Vulnerabilities in CancerR35CA210030 · NCI · DANA-FARBER CANCER INST · PI STEGMAIER, KIMBERLY · 2016 to 2022
$7.3M
Discovery and targeting of apoptosis resistance mechanisms in high-risk T-ALLR01CA193651 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI GUTIERREZ, ALEJANDRO · 2015 to 2024
$4.4M
NCI NIH HHS R01 CA193651NCI NIH HHS R35 CA210030
6 · The paper itself

Abstract

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.

Indexed as

Drug Resistance, NeoplasmSynthetic Lethal MutationsAnimalsAntineoplastic AgentsAsparaginaseCell DeathDose-Response Relationship, DrugGlycogen Synthase Kinase 3 betaHumansJurkat CellsLeukemiaMaleMice, Inbred NODMice, TransgenicPolyethylene GlycolsProteasome Endopeptidase ComplexAntineoplastic AgentsAsparaginaseGlycogen Synthase Kinase 3 betaGSK3B protein, humanpegaspargasePolyethylene GlycolsProteasome Endopeptidase ComplexProtein Kinase InhibitorsWnt3A ProteinWNT3A protein, humanacute leukemiaasparaginaseasparaginedrug resistanceFBXW7GSK3proteasomal degradationprotein ubiquitinationsynthetic lethalityWnt signaling

Identifiers

PMID30991026
PMCPMC6541931
OpenAlexW2953121516

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.