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EPIDEMIOLOGY

Backtracking to the future: unraveling the origins of childhood leukemia

Leukemia volume 38, pages 416–419 (2024)Cite this article

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Most subtypes, as well as most individual CL cases, are presumed to have in utero origins based both on circumstantial evidence and direct measurement of leukemia-causing somatic alterations in biological samples taken shortly after birth. Studies in monozygotic twins, for instance, have demonstrated that CL can develop in utero [4]. Identical translocation events have been detected in twin pairs concordant for KMT2A-rearranged infant ALL or AML, for ETV6::RUNX1 fusion ALL, or for BCR::ABL1 ALL, supporting that the initiating lesion arises in one twin and transfers to the other via shared placental vasculature [4]. In addition, the observed wide variation in age of leukemia onset in twins concordant for ALL [4] and analysis of the clonal evolution of leukemia cells in such twins support a two-hit model of leukemogenesis, with in utero formation of a pre-leukemic clone and postnatal development of additional mutations that drive progression to overt leukemia [2].

Twins concordant for CL are rare, and further insight into the natural history of CL has been gained through backtracking studies using newborn blood samples from children who later developed leukemia. This was first demonstrated by Gale and colleagues, who detected the presence of leukemia-forming KMT2A::AFF1 fusions in the newborn DBS of three ALL patients <2 years of age [5]. In a subsequent study by Wiemels et al., the majority of ETV6::RUNX1 fusion ALL patients were positive for the translocation sequence in newborn dried bloodspots (DBS) [6]. In addition, backtracking of KMT2A-rearranged infant ALL and AML, AML1::ETO in AML, and clonal IGH rearrangements in high hyperdiploid ALL support the prenatal development of these leukemia subtypes (Fig. 1 and reviewed by Marcotte et al. [7]; subtype frequencies derived from Pui et al. [8] and Huang et al. [9]). Results for TCF3::PBX1 fusion have been less consistent [7] and require clarification. Recently described and less common ALL subtypes, including BCR::ABL1-like and translocations of DUX4, ZNF384, and MEF2D as well as most T-cell ALL and AML-defining rearrangements, have yet to be examined at birth (Fig. 1). This is likely due, at least in part, to a lack of access to suitable stored samples. In a recent Perspective by Greaves and colleagues, the in utero origins of ALL in twins discordant for ALL was described, as the same fusion sequence was detected in newborn blood samples from the affected twins as well as their healthy co-twins [10]. Backtracking studies have largely corroborated the findings in twins, supporting the postnatal acquisition of second-hit somatic alterations [11].

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Fig. 1: Childhood leukemia subtypes and backtracking status.
Fig. 2: Aims of the ReCord study, 2021-ongoing.

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Acknowledgements

Supported by a National Institutes of Health grant R01CA262012 (to Drs. de Smith, Wiemels, Mead, Roberts, Roy, and Spector), a Leukemia & Lymphoma Society Scholar Award (de Smith), and a Wellcome Trust Clinical Research Career Development Fellowship and Medical Research Council award (Roy). The authors would like to thank the patients and families who have enrolled in the ReCord study. We would also like to thank Michelle Roesler for coordination of the ReCord study, and Dr. Zhanni Lu for helping to prepare figures for this manuscript.

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Authors and Affiliations

  1. Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    Adam J. de Smith & Joseph L. Wiemels

  2. USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Adam J. de Smith & Joseph L. Wiemels

  3. Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Adam J. Mead

  4. Department of Paediatrics and MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Irene Roberts & Anindita Roy

  5. Department of Haematology, Great Ormond Street Hospital for Children, London, UK

    Anindita Roy

  6. Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, MN, USA

    Logan G. Spector

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de Smith, A.J., Wiemels, J.L., Mead, A.J. et al. Backtracking to the future: unraveling the origins of childhood leukemia. Leukemia 38, 416–419 (2024). https://doi.org/10.1038/s41375-023-02111-8

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