ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications

Jessica Atkins; Anna-Mariya Kukuyan; Monika Toma; Malgorzata Drzewiecka; Umeshkumar Vekariya; Adam Karami; Margaret Nieborowska-Skorska; Reza Nejati; Emir Hadzijusufovic; Peter Valent; Tomasz Stoklosa; Tomasz Sliwinski; Mariusz Wasik; Tomasz Skorski

doi:10.1038/s41375-025-02687-3

ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications

Jessica Atkins
, Anna-Mariya Kukuyan
, Monika Toma
, Malgorzata Drzewiecka
, Umeshkumar Vekariya
, Adam Karami
, Margaret Nieborowska-Skorska
, Reza Nejati
, Emir Hadzijusufovic
, Peter Valent
, Tomasz Stoklosa
, Tomasz Sliwinski
, Mariusz Wasik
, Tomasz Skorski

Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
University of Lodz
Fox Chase Cancer Center
Medical University of Vienna
Medical University of Warsaw

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

4 Scopus citations

Abstract

Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.

Original language	English
Pages (from-to)	2152-2162
Number of pages	11
Journal	Leukemia
Volume	39
Issue number	9
Early online date	Jul 10 2025
DOIs	https://doi.org/10.1038/s41375-025-02687-3
State	Published - Sep 2025

Keywords

Alcohol Dehydrogenase/metabolism
Aldehyde Dehydrogenase, Mitochondrial/metabolism
Animals
DNA Polymerase theta
DNA-Directed DNA Polymerase/metabolism
Formaldehyde/toxicity
Hematopoietic Stem Cells/drug effects
Humans
Mice

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10.1038/s41375-025-02687-3

Cite this

Atkins, J., Kukuyan, A.-M., Toma, M., Drzewiecka, M., Vekariya, U., Karami, A., Nieborowska-Skorska, M., Nejati, R., Hadzijusufovic, E., Valent, P., Stoklosa, T., Sliwinski, T., Wasik, M., & Skorski, T. (2025). ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications. Leukemia, 39(9), 2152-2162. https://doi.org/10.1038/s41375-025-02687-3

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title = "ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications",

abstract = "Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.",

keywords = "Alcohol Dehydrogenase/metabolism, Aldehyde Dehydrogenase, Mitochondrial/metabolism, Animals, DNA Polymerase theta, DNA-Directed DNA Polymerase/metabolism, Formaldehyde/toxicity, Hematopoietic Stem Cells/drug effects, Humans, Mice",

author = "Jessica Atkins and Anna-Mariya Kukuyan and Monika Toma and Malgorzata Drzewiecka and Umeshkumar Vekariya and Adam Karami and Margaret Nieborowska-Skorska and Reza Nejati and Emir Hadzijusufovic and Peter Valent and Tomasz Stoklosa and Tomasz Sliwinski and Mariusz Wasik and Tomasz Skorski",

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doi = "10.1038/s41375-025-02687-3",

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Atkins, J, Kukuyan, A-M, Toma, M, Drzewiecka, M, Vekariya, U, Karami, A, Nieborowska-Skorska, M, Nejati, R, Hadzijusufovic, E, Valent, P, Stoklosa, T, Sliwinski, T, Wasik, M & Skorski, T 2025, 'ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications', Leukemia, vol. 39, no. 9, pp. 2152-2162. https://doi.org/10.1038/s41375-025-02687-3

TY - JOUR

T1 - ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge

T2 - therapeutic implications

AU - Atkins, Jessica

AU - Kukuyan, Anna-Mariya

AU - Toma, Monika

AU - Drzewiecka, Malgorzata

AU - Vekariya, Umeshkumar

AU - Karami, Adam

AU - Nieborowska-Skorska, Margaret

AU - Nejati, Reza

AU - Hadzijusufovic, Emir

AU - Valent, Peter

AU - Stoklosa, Tomasz

AU - Sliwinski, Tomasz

AU - Wasik, Mariusz

AU - Skorski, Tomasz

PY - 2025/9

Y1 - 2025/9

N2 - Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.

AB - Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.

KW - Alcohol Dehydrogenase/metabolism

KW - Aldehyde Dehydrogenase, Mitochondrial/metabolism

KW - Animals

KW - DNA Polymerase theta

KW - DNA-Directed DNA Polymerase/metabolism

KW - Formaldehyde/toxicity

KW - Hematopoietic Stem Cells/drug effects

KW - Humans

KW - Mice

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U2 - 10.1038/s41375-025-02687-3

DO - 10.1038/s41375-025-02687-3

M3 - Article

C2 - 40640557

SN - 0887-6924

VL - 39

SP - 2152

EP - 2162

JO - Leukemia

JF - Leukemia

IS - 9

ER -

ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications

Abstract

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Common Intracellular Toxin Could Help Fight Leukemia

Researchers from Temple University Report on Findings in Hematology (Adh5/aldh2 Dehydrogenases and Dna Polymerase Theta Protect Normal and Malignant Hematopoietic Cells From Formaldehyde Challenge: Therapeutic Implications)

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ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Press/Media

Common Intracellular Toxin Could Help Fight Leukemia

Researchers from Temple University Report on Findings in Hematology (Adh5/aldh2 Dehydrogenases and Dna Polymerase Theta Protect Normal and Malignant Hematopoietic Cells From Formaldehyde Challenge: Therapeutic Implications)

Cite this