Modulation of the ETV6::RUNX1 Gene Fusion Prevalence in Newborns by Corticosteroid Use During Pregnancy

<i>ETV6::RUNX1</i>-positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene <i>ETV6::RUNX1</i> and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit have not yet been determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the <i>ETV6::RUNX1</i> fusion. To this end, we employed a nested interventional cohort study (IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, a Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in the DNA of cord blood samples at delivery (<i>n</i> = 741) using the state-of-the-art GIPFEL (genomic inverse PCR for exploration of ligated breakpoints) technique. A total of 6.5% (<i>n</i> = 48 of 741) of healthy newborns tested positive for <i>ETV6::RUNX1</i>. Our multiple regression analyses showed a trend toward lower <i>ETV6::RUNX1</i> prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with <i>ETV6::RUNX1</i> (adjusted OR 3.9, 95% CI 1.6-9.8) in 39 neonates, particularly if applied before 26 weeks of gestation (OR 7.7, 95% CI 1.08-50) or if betamethasone (OR 4.0, 95% CI 1.4-11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk of developing <i>ETV6::RUNX1</i>+ preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that <i>ETV6::RUNX1</i> preleukemia prevalence may be modulated and potentially prevented.

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Publication Details

Journal
International Journal of Molecular Sciences
Published
2025-03-25
DOI
https://doi.org/10.3390/ijms26072971
Primary Topic
Acute Lymphoblastic Leukemia research
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article
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0.00

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article

Modulation of the ETV6::RUNX1 Gene Fusion Prevalence in Newborns by Corticosteroid Use During Pregnancy

Pablo Menéndez, Helena Castillo‐Ecija, L. Youssef, Arndt Borkhardt et al.
International Journal of Molecular Sciences
Acute Lymphoblastic Leukemia research
article

Modulation of the ETV6::RUNX1 Gene Fusion Prevalence in Newborns by Corticosteroid Use During Pregnancy

Pablo Menéndez, Helena Castillo‐Ecija, L. Youssef, Arndt Borkhardt, Rosa Casas, Ute Fischer, F. Crispi, Clara Bueno, Eduard Vieta, F. Crovetto, Leticia Benítez, Ersen Kameri, Marta Larroya, Eduard Gratacós, Sara Castro‐Barquero, Ramon Estruch, R Borras
article en

Abstract

<i>ETV6::RUNX1</i>-positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene <i>ETV6::RUNX1</i> and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit have not yet been determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the <i>ETV6::RUNX1</i> fusion. To this end, we employed a nested interventional cohort study (IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, a Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in the DNA of cord blood samples at delivery (<i>n</i> = 741) using the state-of-the-art GIPFEL (genomic inverse PCR for exploration of ligated breakpoints) technique. A total of 6.5% (<i>n</i> = 48 of 741) of healthy newborns tested positive for <i>ETV6::RUNX1</i>. Our multiple regression analyses showed a trend toward lower <i>ETV6::RUNX1</i> prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with <i>ETV6::RUNX1</i> (adjusted OR 3.9, 95% CI 1.6-9.8) in 39 neonates, particularly if applied before 26 weeks of gestation (OR 7.7, 95% CI 1.08-50) or if betamethasone (OR 4.0, 95% CI 1.4-11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk of developing <i>ETV6::RUNX1</i>+ preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that <i>ETV6::RUNX1</i> preleukemia prevalence may be modulated and potentially prevented.

International Journal of Molecular SciencesVol. 26(7)
Institució Catalana de Recerca i Estudis Avançats (ES), Hospital Sant Joan de Déu Barcelona (ES), German Cancer Research Center (DE), Heidelberg University (DE), Instituto de Salud Carlos III (ES), Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (ES), Josep Carreras Leukaemia Research Institute (ES), Centro de Investigación Biomédica en Red de Salud Mental (ES), Red de Investigación en Actividades Preventivas y Promoción de la Salud (ES), DKFZ-ZMBH Alliance (DE), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Institut de Recerca Sant Joan de Déu, Heinrich Heine University Düsseldorf (DE), Universitat de Barcelona (ES)
“la Caixa” Foundation, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Universitat de Barcelona, Deutsche Krebshilfe, Deutsche Kinderkrebsstiftung, Instituto de Salud Carlos III
Openalex Percentile: Top 92%
Acute Lymphoblastic Leukemia research
DOIOpen Access PDFOpenAlex
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