Evidence map›Paper›PMID 41850232›Full record

ArticleCell reports. Medicine2026

Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia.

Bac Viet Le, Umeshkumar Vekariya, Monika M Toma, Margaret Nieborowska-Skorska, Marie-Christine Caron, Malgorzata Gozdecka, Zayd Haydar, Martin Walsh, Jayashri Ghosh, Elaine Vaughan-Williams and 18 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports. Medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

28 authors.

Bac Viet LeFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Umeshkumar VekariyaFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Monika M TomaFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Margaret Nieborowska-SkorskaFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Marie-Christine CaronCHU de Québec Research Centre (Oncology Division, Hôpital Enfant-Jesus) and Laval University Cancer Research Center, Québec City, QC G1V 4G2, Canada.
Malgorzata GozdeckaWellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
Zayd HaydarFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Martin WalshCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA; Nuclear Dynamics and Cancer Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Jayashri GhoshFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Elaine Vaughan-WilliamsFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Paulina Podszywalow-BartnickaLaboratory of Cytometry, Nencki Institute of Experimental Biology Polish Academy of Sciences, 02-093 Warsaw, Poland.
Anna-Mariya KukuyanFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Sylwia ZiolkowskaFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Jessica AtkinsFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Emir HadzijusufovicDepartment for Companion Animals & Horses, Clinic for Internal Medicine and Infectious Diseases, University of Veterinary Medicine Vienna, Vienna 1210, Austria; Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna 1090, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna 1990, Austria.
Gurushankar ChandramoulyDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Reza NejatiDepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Katarzyna PiwockaLaboratory of Cytometry, Nencki Institute of Experimental Biology Polish Academy of Sciences, 02-093 Warsaw, Poland.
Richard PomerantzDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
George S VassiliouWellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
Brian J P HuntlyWellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK.
Peter ValentDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna 1090, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna 1990, Austria.
Mariusz WasikDepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Alfonso BellacosaCancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
Jean-Yves MassonCHU de Québec Research Centre (Oncology Division, Hôpital Enfant-Jesus) and Laval University Cancer Research Center, Québec City, QC G1V 4G2, Canada.
Gaorav P GuptaLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Grant A ChallenDivision of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Tomasz SkorskiFels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: tskorski@temple.edu.

Funding

NCI NIH HHS R01 CA244044
6 · The paper itself

Abstract

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are refractory to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double-strand breaks (DSBs) and stalled replication forks, rendering them dependent on DNA damage response (DDR). We report here that DNA polymerase theta (Polθ), a key element in DSB repair by end-joining (Polθ-mediated end-joining [TMEJ]) and in fork restarting, promotes survival and proliferation of DNMT3Amut leukemia cells. Polθ is overexpressed in DNMT3Amut leukemia cells due to abrogation of PARP1 PARylation-dependent UBE2O E3 ligase-mediated ubiquitination and proteasomal degradation of Polθ. In addition, PARP1-mediated recruitment of the SMARCAD1-MSH2/MSH3 repressive complex to DSBs is diminished in DNMT3Amut leukemia cells, which facilitates association of Polθ with DNA damage. Polθ inhibitors enhance the anti-leukemic effects of standard drugs such as FLT3 kinase inhibitor quizartinib, cytarabine ± doxorubicin, and etoposide in vitro and in mice with DNMT3Amut leukemia. Altogether, Polθ is an attractive target in DNMT3Amut hematological malignancies.

Indexed as

DNA (Cytosine-5-)-MethyltransferasesDNA-Directed DNA PolymeraseLeukemiaAnimalsCell Line, TumorCell ProliferationDNA Breaks, Double-StrandedDNA DamageDNA Methyltransferase 3ADNA Polymerase thetaHumansMiceMutationUbiquitinationDNA (Cytosine-5-)-MethyltransferasesDNA-Directed DNA PolymeraseDNA Methyltransferase 3ADNA Polymerase thetaDNMT3A protein, humanDnmt3a protein, mouseDNA polymerase thetaDNMT3A-deficient acute myeloid leukemiaPARP1replication forkTMEJubiquitination

Identifiers

PMID41850232
PMCPMC13006424

What Socratic 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 Socratic graph.