dc.contributor.author | Beneforti, L | |
dc.contributor.author | Dander, E | |
dc.contributor.author | Bresolin, S | |
dc.contributor.author | Bueno, C | |
dc.contributor.author | Acunzo, D | |
dc.contributor.author | Bertagna, M | |
dc.contributor.author | Ford, A | |
dc.contributor.author | Gentner, B | |
dc.contributor.author | Kronnie, GT | |
dc.contributor.author | Vergani, P | |
dc.contributor.author | Menéndez, P | |
dc.contributor.author | Biondi, A | |
dc.contributor.author | D'Amico, G | |
dc.contributor.author | Palmi, C | |
dc.contributor.author | Cazzaniga, G | |
dc.date.accessioned | 2020-08-05T11:30:07Z | |
dc.date.issued | 2020-01-01 | |
dc.identifier.citation | British journal of haematology, 2020, 190 (2), pp. 262 - 273 | |
dc.identifier.issn | 0007-1048 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3903 | |
dc.identifier.eissn | 1365-2141 | |
dc.identifier.doi | 10.1111/bjh.16523 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 262 - 273 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | Wiley | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | Pro-inflammatory cytokines favor the emergence of ETV6-RUNX1-positive pre-leukemic cells in a model of mesenchymal niche. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-01-13 | |
rioxxterms.versionofrecord | 10.1111/bjh.16523 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2020-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | British journal of haematology | |
pubs.issue | 2 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Biology of Childhood Leukaemia | |
pubs.publication-status | Published | |
pubs.volume | 190 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Biology of Childhood Leukaemia | |
dc.contributor.icrauthor | Ford, Anthony | |