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Pro-inflammatory cytokines favor the emergence of ETV6-RUNX1-positive pre-leukemic cells in a model of mesenchymal niche.

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Date
2020-07
ICR Author
Ford, Anthony
Author
Beneforti, L
Dander, E
Bresolin, S
Bueno, C
Acunzo, D
Bertagna, M
Ford, A
Gentner, B
Kronnie, GT
Vergani, P
Menéndez, P
Biondi, A
D'Amico, G
Palmi, C
Cazzaniga, G
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Type
Journal Article
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Abstract
ETV6-RUNX1 (E/R) fusion gene, arising in utero from translocation t(12;21)(p13:q22), is the most frequent alteration in childhood acute lymphoblastic leukemia (ALL). However, E/R is insufficient to cause overt leukemia since it generates a clinically silent pre-leukemic clone which persists in the bone marrow but fails to out-compete normal progenitors. Conversely, pre-leukemic cells show increased susceptibility to transformation following additional genetic insults. Infections/inflammation are the most accredited triggers for mutations accumulation and leukemic transformation in E/R+ pre-leukemic cells. However, precisely how E/R and inflammation interact in promoting leukemia is still poorly understood. Here we demonstrate that IL6/TNFα/ILβ pro-inflammatory cytokines cooperate with BM-MSC in promoting the emergence of E/R+ Ba/F3 over their normal counterparts by differentially affecting their proliferation and survival. Moreover, IL6/TNFα/ILβ-stimulated BM-MSC strongly attract E/R+ Ba/F3 in a CXCR2-dependent manner. Interestingly, E/R-expressing human CD34+ IL7R+ progenitors, a putative population for leukemia initiation during development, were preserved in the presence of BM-MSC and IL6/TNFα/ILβ compared to their normal counterparts. Finally, the extent of DNA damage increases within the inflamed niche in both control and E/R-expressing Ba/F3, potentially leading to transformation in the apoptosis-resistant pre-leukemic clone. Overall, our data provide new mechanistic insights into childhood ALL pathogenesis.
URI
https://repository.icr.ac.uk/handle/internal/3903
DOI
https://doi.org/10.1111/bjh.16523
Collections
  • Molecular Pathology
Research team
Biology of Childhood Leukaemia
Language
eng
Date accepted
2020-01-13
License start date
2020-07
Citation
British journal of haematology, 2020, 190 (2), pp. 262 - 273

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