Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations

Behrens YL, Reinkens T, Hofmann W, Gumann A, Förster A, Gaschler L, Ghete T, Strasser R, Espenkötter J, Haermeyer B, Losch M, Sembill S, Wotschofsky Z, von Hörsten S, Schuh W, Di Donato N, Suttorp M, Krumbholz M, Ripperger T, Schlegelberger B, Göhring G, Metzler M, Karow A (2025)

Publication Language: English

Publication Type: Journal article

Publication year: 2025

Journal

British Journal of Haematology Wiley-Blackwell

Book Volume: 207

Pages Range: 141-150

Journal Issue: 1

DOI: 10.1111/bjh.20133

Abstract

Paediatric blast-phase chronic myeloid leukaemia (CML-BP) is a rare and serious condition. Of 231 paediatric patients enrolled in the German CML-PAED-II registry between January 2007 and September 2023, 25 individuals (11%) were diagnosed with CML-BP. To identify genetic variants associated with early onset and disease transformation, we performed whole genome sequencing (WGS), deep targeted sequencing and cytogenetic analyses in 19 cases with de novo (n = 11) or secondary (n = 8) CML-BP and sufficient available biomaterial. Copy number variants (CNVs) were more frequent than single nucleotide variants (SNVs) and more prevalent in secondary than in de novo CML-BP. Recurrent pathogenic somatic SNVs were observed in ABL1 (n = 5, 24%), RUNX1 (n = 2, 12%) and ASXL1 (n = 2, 12%). Nine patients (47%) carried pathogenic germline (n = 8) or somatic (n = 1) variants in either of the genes ATM, CHEK2, FANCM, HERC2, NBN, RAD54B, RECQL4, SETD2 or TP63 belonging to the DNA damage response (DDR). Within a comparison cohort of 19 patients with chronic phase paediatric CML, only one individual (5%) exhibited a pathogenic DDR germline variant. Our study provides novel pathogenetic insights into paediatric CML-BP. The identification of pathogenic DDR-associated germline variants suggests a genetic predisposition with potential implications for patients and families concerning cancer treatment and surveillance.

Authors with CRIS profile

Amelie Gumann Department of Paediatrics and Adolescent Medicine Manuel Hann
Laura Gaschler Medizinische Fakultät Denisia-Tabita Ghete Department of Paediatrics and Adolescent Medicine Stephanie Sembill Department of Paediatrics and Adolescent Medicine Stephan von Hörsten Professur für Experimentelle Biomedizin Wolfgang Schuh Department of Molecular Immunology Manuela Krumbholz Department of Paediatrics and Adolescent Medicine Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie Axel Karow Department of Paediatrics and Adolescent Medicine

Involved external institutions

Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) amedes Medizinische Dienstleistungen GmbH DE Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden DE Germany (DE)

How to cite

APA:

Behrens, Y.L., Reinkens, T., Hofmann, W., Gumann, A., Förster, A., Gaschler, L.,... Karow, A. (2025). Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations. British Journal of Haematology, 207(1), 141-150. https://doi.org/10.1111/bjh.20133

MLA:

Behrens, Yvonne Lisa, et al. "Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations." British Journal of Haematology 207.1 (2025): 141-150.

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