Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia

Aleksandra E. Kamizela, Daniel Leongamornlert, Nicholas Williams, Xin Wang, Kudzai Nyamondo, Kevin Dawson, Michael Spencer Chapman, Jing Guo, Joe Lee, Karim Mane, Kate Milne, Anthony R. Green, Timothy Chevassut, Peter J. Campbell, Patrick T. Ellinor, Brian J. P. Huntly, E. Joanna Baxter and Jyoti Nangalia ()
Additional contact information
Aleksandra E. Kamizela: Wellcome Sanger Institute
Daniel Leongamornlert: Wellcome Sanger Institute
Nicholas Williams: Wellcome Sanger Institute
Xin Wang: Wellcome Sanger Institute
Kudzai Nyamondo: Wellcome Sanger Institute
Kevin Dawson: Wellcome Sanger Institute
Michael Spencer Chapman: Wellcome Sanger Institute
Jing Guo: Wellcome Sanger Institute
Joe Lee: Wellcome Sanger Institute
Karim Mane: Wellcome Sanger Institute
Kate Milne: Cambridge University Hospitals NHS Trust
Anthony R. Green: University of Cambridge
Timothy Chevassut: Brighton and Sussex Medical School
Peter J. Campbell: Wellcome Sanger Institute
Patrick T. Ellinor: Broad Institute of MIT and Harvard
Brian J. P. Huntly: University of Cambridge
E. Joanna Baxter: Cambridge University Hospitals NHS Trust
Jyoti Nangalia: Wellcome Sanger Institute

Nature, 2025, vol. 640, issue 8060, 982-990

Abstract: Abstract Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer1,2. However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1, were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3–14 years (confidence interval 2–16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-08817-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:640:y:2025:i:8060:d:10.1038_s41586-025-08817-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-08817-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().