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Peer-reviewedCC BY 4.0HemaSphere

Lineage switch in childhood leukemia

  • Katharina Daugs1,2
  • Anna Prazmo1
  • Anindita Roy1,3,4
  • Arndt Borkhardt2
4 affiliations
  1. 1Department of Paediatrics University of Oxford Oxford United Kingdom
  2. 2Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany
  3. 3MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine University of Oxford Oxford United Kingdom
  4. 4Department of Haematology Great Ormond Street Hospital for Children London United Kingdom
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Abstract

Lineage switch (LS) is a rare but aggressive immunophenotypic transformation of acute leukemia associated with limited therapeutic options and poor clinical outcome. Although LS has been increasingly recognized in the era of CD19‐directed immunotherapies, its biological basis remains incompletely understood. Most reported pediatric LS cases occur in KMT2A‐rearranged (KMT2A‐r) leukemia, highlighting a link between developmental origin and lineage plasticity. In this review, we provide a comprehensive overview of the clinical, molecular, epigenetic, and cellular determinants of pediatric LS. We systematically reviewed the literature and identified 201 pediatric LS cases reported between 1994 and 2026. Among these, 70.1% involved B‐lymphoblastic leukemias switching to acute myeloid leukemias, with KMT2A‐r (47.8%) and DUX4‐rearranged (14.9%) leukemias representing the most frequent genetic subtypes. Across the published cases, LS occurred earlier following blinatumomab exposure than after chimeric antigen receptor cells or chemotherapy alone. We discuss current mechanistic concepts underlying LS, including epigenetic remodeling, chromatin regulation, developmental programs, the cell‐of‐origin, and therapy‐associated selective pressures that promote lineage plasticity. By integrating clinical evidence with current insights into leukemia biology, this review provides a framework for understanding LS in pediatric leukemias and highlights priorities for future research, early detection, and development of preventive and/or therapeutic strategies.

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Cite

BibTeXRIS
BibTeX
@article{daugs2026lineage,
  title = {{Lineage switch in childhood leukemia}},
  author = {Katharina Daugs and Anna Prazmo and Anindita Roy and Arndt Borkhardt},
  journal = {HemaSphere},
  year = {2026},
  month = nov,
  doi = {10.1002/hem3.70528},
  url = {https://doi.org/10.1002/hem3.70528},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Lineage switch in childhood leukemia
AU  - Katharina Daugs
AU  - Anna Prazmo
AU  - Anindita Roy
AU  - Arndt Borkhardt
PY  - 2026
DA  - 2026/11/04
JO  - HemaSphere
DO  - 10.1002/hem3.70528
UR  - https://doi.org/10.1002/hem3.70528
AB  - Lineage switch (LS) is a rare but aggressive immunophenotypic transformation of acute leukemia associated with limited therapeutic options and poor clinical outcome. Although LS has been increasingly recognized in the era of CD19‐directed immunotherapies, its biological basis remains incompletely understood. Most reported pediatric LS cases occur in KMT2A‐rearranged (KMT2A‐r) leukemia, highlighting a link between developmental origin and lineage plasticity. In this review, we provide a comprehensive overview of the clinical, molecular, epigenetic, and cellular determinants of pediatric LS. We systematically reviewed the literature and identified 201 pediatric LS cases reported between 1994 and 2026. Among these, 70.1% involved B‐lymphoblastic leukemias switching to acute myeloid leukemias, with KMT2A‐r (47.8%) and DUX4‐rearranged (14.9%) leukemias representing the most frequent genetic subtypes. Across the published cases, LS occurred earlier following blinatumomab exposure than after chimeric antigen receptor cells or chemotherapy alone. We discuss current mechanistic concepts underlying LS, including epigenetic remodeling, chromatin regulation, developmental programs, the cell‐of‐origin, and therapy‐associated selective pressures that promote lineage plasticity. By integrating clinical evidence with current insights into leukemia biology, this review provides a framework for understanding LS in pediatric leukemias and highlights priorities for future research, early detection, and development of preventive and/or therapeutic strategies.
SN  - 2572-9241
ER  -