Complex genotype-phenotype relationships shape the response to treatment of down syndrome childhood acute lymphoblastic leukaemia
(2025) In Scientific Reports 15(1).- Abstract
Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we... (More)
Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this ‘eco-system’ and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.
(Less)
- author
- Lutz, Christoph
; Turati, Virginia A.
LU
; Clifford, Ruth
; Woll, Petter S.
; Stiehl, Thomas
; Castor, Anders
; Clark, Sally A.
; Ferry, Helen
; Buckle, Veronica
; Trumpp, Andreas
; Ho, Anthony
; Marciniak-Czochra, Anna
; Herrero, Javier
LU
; Schuh, Anna
; Jacobsen, Sten Eirik W.
and Enver, Tariq
LU
(Less) - organization
- publishing date
- 2025-12
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 15
- issue
- 1
- article number
- 42018
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:41291054
- scopus:105023206219
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-025-28779-9
- language
- English
- LU publication?
- yes
- id
- b30d920d-d1cb-40c3-b1ac-cb3a00378517
- date added to LUP
- 2026-01-14 13:29:26
- date last changed
- 2026-02-11 16:12:33
@article{b30d920d-d1cb-40c3-b1ac-cb3a00378517,
abstract = {{<p>Extensive genetic and epigenetic variegation has been demonstrated in many malignancies. Importantly, their interplay has the potential to contribute to disease progression and treatment resistance. To shed light on the complex relationships between these different sources of intra-tumour heterogeneity, we explored their relative contributions to the evolutionary dynamics of Acute Lymphoblastic Leukaemia (ALL) in children with Down syndrome, which has particularly poor prognosis. We quantified the tumour propagating potential of genetically distinct sub-clones using serial transplantation assays and SNP-arrays. While most leukaemias were characterized by a single dominant subclone, others were highly heterogeneous. Importantly, we provide clear and direct evidence that genotypes and phenotypes with functional relevance to leukemic progression and treatment resistance can co-segregate within the disease. Hence, individual genetic lesions can be restricted to well-defined cell immunophenotypes, corresponding to different stages of the leukemic differentiation hierarchy and varied proliferation potentials. As a result of this difference in fitness, which can be accurately quantified via competitive transplantation assays, matching diagnostic, post-treatment, and relapse leukaemias can be dominated by different genotypes, including pre-leukemic clones persisting throughout the disease progression and treatment. Intriguingly, plasticity also appears to be a temporally defined property that can segregate with genotype. These results suggest that Down Syndrome ALL should be viewed as a complex matrix of cells exhibiting genetic and epigenetic heterogeneity that foster extensive clonal evolution and competition. Therapeutic intervention reshapes this ‘eco-system’ and may provide the right conditions for the preferential expansion of selected compartments and subsequently relapse.</p>}},
author = {{Lutz, Christoph and Turati, Virginia A. and Clifford, Ruth and Woll, Petter S. and Stiehl, Thomas and Castor, Anders and Clark, Sally A. and Ferry, Helen and Buckle, Veronica and Trumpp, Andreas and Ho, Anthony and Marciniak-Czochra, Anna and Herrero, Javier and Schuh, Anna and Jacobsen, Sten Eirik W. and Enver, Tariq}},
issn = {{2045-2322}},
language = {{eng}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{Complex genotype-phenotype relationships shape the response to treatment of down syndrome childhood acute lymphoblastic leukaemia}},
url = {{http://dx.doi.org/10.1038/s41598-025-28779-9}},
doi = {{10.1038/s41598-025-28779-9}},
volume = {{15}},
year = {{2025}},
}