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ACUTE LYMPHOBLASTIC LEUKEMIA

All genetic subtypes of B-cell acute lymphoblastic leukemia exhibit increased incidence rates in children with Down syndrome

Leukemia volume 39, pages 1516–1519 (2025)Cite this article

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Children with Down syndrome (DS) have a 20-fold increased risk and 2% lifetime risk of developing B-cell acute lymphoblastic leukemia (B-ALL) [1,2,3]. Despite improvements over time, survival in DS-ALL remains consistently 10 to 20% lower compared to non-DS-ALL, due to both increased relapse and more frequent and severe treatment-related toxicities [4,5,6].

Notably, the somatic genomic landscape of DS-ALL differs from that of non-DS-ALL. CRLF2 rearrangements (CRLF2-r) and JAK2 mutations are more frequent in DS-ALL, whereas most other subtypes are less frequent [4, 7,8,9,10,11]. A recent study of 295 DS-ALL cases in comparison to 2 257 non-DS-ALL cases showed that CRLF2-r was 9 times more frequent in DS-ALL (54.2% vs 6.0%), along with an increased prevalence of JAK2 mutations (26.2% vs 3.5%) [12]. This study also identified eight additional subtypes with significantly different frequencies between DS-ALL and non-DS-ALL: C/EBPalt and IGH::IGF2BP1 subtypes were highly enriched in the DS-ALL cohort, whereas high hyperdiploid, BCR::ABL1-like, BCR::ABL1, KMT2A-rearranged (KMT2A-r), DUX4-rearranged (DUX4-r), and intrachromosomal amplification of chromosome 21 (iAMP21) subtypes were underrepresented in DS-ALL compared with non-DS-ALL.

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Fig. 1: Incidence rate ratios (IRR) and 95% confidence intervals (CI) comparing the incidence of B-cell acute lymphoblastic leukemia (B-ALL) risk groups between Down syndrome (DS) and non-DS patients.

Data availability

The published Children’s Oncology Group data can be found in Rabin et al., [5], and the aggregated data from GOBACK Study are available from the corresponding authors upon reasonable request. Restrictions apply to individual-level data, which were used with permission of the participating states. Individual-level data are available by application to: Arkansas Reproductive Health Monitoring System, Florida Department of Health, Massachusetts Department of Health, Michigan Department of Health and Human Services, New Jersey Department of Health, North Carolina Department of Public Health, Oklahoma State Department of Health, South Carolina Department of Health and Environmental Control, and Texas Department of State Health Services.

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Acknowledgements

The authors express their heartfelt appreciation to the investigators and staff whose invaluable contributions were instrumental in the development of the GOBACK Registry Linkage Cohort.

Funding

This work was supported by the Cancer Prevention and Research Institute of Texas (RP210027 awarded to C.J.H.), the Rally Foundation for Childhood Cancer Research (23CDNO5 awarded to J.M.S.), and the National Institutes of Health (R01CA284531 awarded to C.D.H. and P.J.L., and R01CA249867 awarded to K.R.R. and P.J.L.). Additionally, the Texas Birth Defects Epidemiology and Surveillance Branch received partial funding through the Title V Block Grant administered by the Texas Department of State Health Services.

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Author notes

  1. These authors contributed equally: Karen R. Rabin, Philip J. Lupo.

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Ching-Ju Hsu, Jeremy M. Schraw, Michael E. Scheurer, Karen R. Rabin & Philip J. Lupo

  2. Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Tania A. Desrosiers

  3. Department of Biostatistics and Epidemiology, Hudson College of Public Health, University of Oklahoma Health Sciences, Oklahoma City, OK, USA

    Amanda E. Janitz

  4. Chiles Center, College of Public Health, University of South Florida, Tampa, FL, USA

    Russell S. Kirby, Jason L. Salemi & Jean Paul Tanner

  5. Division for Surveillance, Research, and Promotion of Perinatal Health, Massachusetts Department of Public Health, Boston, MA, USA

    Eirini Nestoridi & Mahsa M. Yazdy

  6. Department of Epidemiology, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Wendy N. Nembhard

  7. Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, TX, USA

    Charles Shumate

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  1. Ching-Ju Hsu
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Contributions

C.J.H.: Data curation, formal analysis, visualization, writing-original draft, and writing-review and editing. J.M.S: Conceptualization, data curation, funding acquisition, methodology, supervision, and writing–review and editing. T.A.D., A.E.J., R.S.K., E.N., W.N.N., J.L.S., C.S., J.P.T., and M.M.Y: Data curation, resources, and writing–review and editing. M.E.S: Conceptualization, data curation, methodology, resources, supervision and writing–review and editing. K.R.R., and P.J.L: Conceptualization, data curation, funding acquisition, methodology, project administration, resources, supervision, and writing–review and editing.

Corresponding authors

Correspondence to Karen R. Rabin or Philip J. Lupo.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study complied with the principles of the Declaration of Helsinki and was approved by the Institutional Review Boards of participating institutions. The requirement for written informed consent was waived as it involved secondary analysis of de-identified data.

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Hsu, CJ., Schraw, J.M., Desrosiers, T.A. et al. All genetic subtypes of B-cell acute lymphoblastic leukemia exhibit increased incidence rates in children with Down syndrome. Leukemia 39, 1516–1519 (2025). https://doi.org/10.1038/s41375-025-02602-w

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