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; Paulina Podszywalow-Bartnicka; Anna-Mariya Kukuyan; Sylwia Ziolkowska; Jessica Atkins; Emir Hadzijusufovic; Gurushankar Chandramouly; Reza Nejati; Katarzyna Piwocka; Richard Pomerantz; George S. Vassiliou; Brian J. P. Huntly; Peter Valent; Mariusz Wasik; Alfonso Bellacosa; Jean-Yves Masson; Gaorav P. Gupta; Grant A. Challen; Tomasz Skorski

doi:10.1016/j.xcrm.2026.102687

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
, Paulina Podszywalow-Bartnicka
, Anna-Mariya Kukuyan
, Sylwia Ziolkowska
, Jessica Atkins
, Emir Hadzijusufovic
, Gurushankar Chandramouly
, Reza Nejati
, Katarzyna Piwocka
, Richard Pomerantz
, George S. Vassiliou

Brian J. P. Huntly, Peter Valent, Mariusz Wasik, Alfonso Bellacosa, Jean-Yves Masson, Gaorav P. Gupta, Grant A. Challen, Tomasz Skorski

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	102687
Pages (from-to)	102687
Number of pages	29
Journal	Cell Reports Medicine
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.xcrm.2026.102687 https://doi.org/10.1016/j.xcrm.2026.102687
State	Published - Mar 17 2026

Keywords

Animals
Cell Line, Tumor
Cell Proliferation/drug effects
DNA (Cytosine-5-)-Methyltransferases/deficiency
DNA Breaks, Double-Stranded
DNA Damage
DNA Methyltransferase 3A
DNA-Directed DNA Polymerase/metabolism
Humans
Leukemia/drug therapy
Mice
Mutation/genetics
Ubiquitination

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Le, B. V., Vekariya, U., Toma, M. M., Nieborowska-Skorska, M., Caron, M.-C., Gozdecka, M., Haydar, Z., Walsh, M., Ghosh, J., Vaughan-Williams, E., Podszywalow-Bartnicka, P., Kukuyan, A.-M., Ziolkowska, S., Atkins, J., Hadzijusufovic, E., Chandramouly, G., Nejati, R., Piwocka, K., Pomerantz, R., ... Skorski, T. (2026). Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia. Cell Reports Medicine, 7(3), 102687. Article 102687. https://doi.org/10.1016/j.xcrm.2026.102687, https://doi.org/10.1016/j.xcrm.2026.102687

@article{c500dcedb5b844b7843996816404a7e9,

title = "Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia",

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.",

keywords = "Animals, Cell Line, Tumor, Cell Proliferation/drug effects, DNA (Cytosine-5-)-Methyltransferases/deficiency, DNA Breaks, Double-Stranded, DNA Damage, DNA Methyltransferase 3A, DNA-Directed DNA Polymerase/metabolism, Humans, Leukemia/drug therapy, Mice, Mutation/genetics, Ubiquitination",

author = "Le, \{Bac Viet\} and Umeshkumar Vekariya and Toma, \{Monika M.\} and Margaret Nieborowska-Skorska and Marie-Christine Caron and Malgorzata Gozdecka and Zayd Haydar and Martin Walsh and Jayashri Ghosh and Elaine Vaughan-Williams and Paulina Podszywalow-Bartnicka and Anna-Mariya Kukuyan and Sylwia Ziolkowska and Jessica Atkins and Emir Hadzijusufovic and Gurushankar Chandramouly and Reza Nejati and Katarzyna Piwocka and Richard Pomerantz and Vassiliou, \{George S.\} and Huntly, \{Brian J. P.\} and Peter Valent and Mariusz Wasik and Alfonso Bellacosa and Jean-Yves Masson and Gupta, \{Gaorav P.\} and Challen, \{Grant A.\} and Tomasz Skorski",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/",

year = "2026",

month = mar,

day = "17",

doi = "10.1016/j.xcrm.2026.102687",

language = "English",

volume = "7",

pages = "102687",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "3",

}

Le, BV, Vekariya, U, Toma, MM, Nieborowska-Skorska, M, Caron, M-C, Gozdecka, M, Haydar, Z, Walsh, M, Ghosh, J, Vaughan-Williams, E, Podszywalow-Bartnicka, P, Kukuyan, A-M, Ziolkowska, S, Atkins, J, Hadzijusufovic, E, Chandramouly, G, Nejati, R, Piwocka, K, Pomerantz, R, Vassiliou, GS, Huntly, BJP, Valent, P, Wasik, M , Bellacosa, A, Masson, J-Y, Gupta, GP, Challen, GA & Skorski, T 2026, 'Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia', Cell Reports Medicine, vol. 7, no. 3, 102687, pp. 102687. https://doi.org/10.1016/j.xcrm.2026.102687, https://doi.org/10.1016/j.xcrm.2026.102687

TY - JOUR

T1 - Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia

AU - Le, Bac Viet

AU - Vekariya, Umeshkumar

AU - Toma, Monika M.

AU - Nieborowska-Skorska, Margaret

AU - Caron, Marie-Christine

AU - Gozdecka, Malgorzata

AU - Haydar, Zayd

AU - Walsh, Martin

AU - Ghosh, Jayashri

AU - Vaughan-Williams, Elaine

AU - Podszywalow-Bartnicka, Paulina

AU - Kukuyan, Anna-Mariya

AU - Ziolkowska, Sylwia

AU - Atkins, Jessica

AU - Hadzijusufovic, Emir

AU - Chandramouly, Gurushankar

AU - Nejati, Reza

AU - Piwocka, Katarzyna

AU - Pomerantz, Richard

AU - Vassiliou, George S.

AU - Huntly, Brian J. P.

AU - Valent, Peter

AU - Wasik, Mariusz

AU - Bellacosa, Alfonso

AU - Masson, Jean-Yves

AU - Gupta, Gaorav P.

AU - Challen, Grant A.

AU - Skorski, Tomasz

PY - 2026/3/17

Y1 - 2026/3/17

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Line, Tumor

KW - Cell Proliferation/drug effects

KW - DNA (Cytosine-5-)-Methyltransferases/deficiency

KW - DNA Breaks, Double-Stranded

KW - DNA Damage

KW - DNA Methyltransferase 3A

KW - DNA-Directed DNA Polymerase/metabolism

KW - Humans

KW - Leukemia/drug therapy

KW - Mice

KW - Mutation/genetics

KW - Ubiquitination

UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:001722067300001&DestLinkType=FullRecord&DestApp=WOS_CPL

U2 - 10.1016/j.xcrm.2026.102687

DO - 10.1016/j.xcrm.2026.102687

M3 - Article

C2 - 41850232

SN - 2666-3791

VL - 7

SP - 102687

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 3

M1 - 102687

ER -

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

Abstract

Keywords

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Data on Leukemia Detailed by Researchers at Temple University (Pol9 Activity Modulates Sensitivity To Standard Therapies In Dnmt3a-deficient Leukemia)

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

Abstract

Keywords

Access to Document

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Data on Leukemia Detailed by Researchers at Temple University (Pol9 Activity Modulates Sensitivity To Standard Therapies In Dnmt3a-deficient Leukemia)

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