Evidence map›Paper›PMID 39198401›Full record

ArticleNature communications2024

TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells.

Peter Truong, Sylvie Shen, Swapna Joshi, Md Imtiazul Islam, Ling Zhong, Mark J Raftery, Ali Afrasiabi, Hamid Alinejad-Rokny, Mary Nguyen, Xiaoheng Zou and 16 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
–field-weighted citation impact
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

12 citing papers in PubMed.

  1. Trial
  2. Review
  3. Article
  4. Article
  5. Article
  6. Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β-Thalassemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  7. Review
  8. Review
  9. Article
  10. Article
  11. Immune regulation by the SUMO family.Nature reviews. Immunology · 2025
    Review
  12. Chromatin Perturbation Promotes Susceptibility to Hypomethylating Agents.bioRxiv : the preprint server for biology · 2025
    Article
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

26 authors.

Peter TruongSchool of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.ORCID 0000-0002-0698-5029
Sylvie ShenSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Swapna JoshiSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Md Imtiazul IslamSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Ling ZhongBioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia.
Mark J RafteryBioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia.
Ali AfrasiabiUNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.
Hamid Alinejad-RoknyUNSW BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, Australia.ORCID 0000-0002-8999-7702
Mary NguyenSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Xiaoheng ZouSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Golam Sarower BhuyanSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Chowdhury H SarowarSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.
Elaheh S GhodousiSchool of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
Olivia StonehouseSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.ORCID 0000-0002-3694-8640
Sara MohamedSchool of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
Cara E ToscanSchool of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
Patrick ConnertySchool of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
Purvi M KakadiaLeukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
Stefan K BohlanderLeukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.ORCID 0000-0002-2202-9088
Katharine A MichieStructural Biology Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia.ORCID 0000-0002-2133-2237
Jonas LarssonDivision of Molecular Medicine and Gene Therapy, Lund Stem Cell Centre, Lund University, Lund, Sweden.ORCID 0000-0001-9198-7434
Richard B LockSchool of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
Carl R WalkleySt Vincent's Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia.ORCID 0000-0002-4784-9031
Julie A I ThomsSchool of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia.ORCID 0000-0002-4876-7230
Christopher J Jolly *School of Biomedical Sciences, UNSW Sydney, Sydney, NSW, Australia. c.jolly@unsw.edu.au.
John E Pimanda *School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia. jpimanda@unsw.edu.au.ORCID 0000-0002-0509-8962

Funding

Cancer Institute NSW (Cancer Institute New South Wales) TPG2152Department of Health | National Health and Medical Research Council (NHMRC) GNT2011627
6 · The paper itself

Abstract

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML.

Indexed as

CRISPR-Cas SystemsDrug Resistance, NeoplasmLeukemia, Myeloid, AcuteMyelodysplastic SyndromesAnimalsCell Line, TumorDNA (Cytosine-5-)-Methyltransferase 1DNA DamageDNA MethylationFemaleHumansMiceSumoylationUbiquitin-Protein LigasesXenograft Model Antitumor AssaysDNA (Cytosine-5-)-Methyltransferase 1DNMT1 protein, humanUbiquitin-Protein Ligases

Identifiers

PMID39198401
PMCPMC11358519

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.