Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 190, Issue 2, Pages 262-273Publisher
WILEY
DOI: 10.1111/bjh.16523
Keywords
ALL; ETV6-RUNX1; pre-leukemia; MSC; inflammation
Categories
Funding
- Fondazione Tettamanti
- Fondazione Cariplo [2018-0339]
- Associazione Italiana Ricerca sul Cancro (AIRC) [21999, 15494]
- Beat Leukemia Foundation
- European Research Council [CoG-2014-646903, PoC-2018-811220]
- Agencia Estatal de Investigacion/European Regional Development Fund [SAF2016-80481-R, SAF2016-75442-R]
- Catalunya Government [SGR330]
- Asociacion Espanola Contra el Cancer
- Beca FERO
- ISCIII/FEDER [PI17/01028]
- Societa Italiana Ematologia Sperimentale (SIES)
- Bianchi Industrial
- Catalunya Government (PERIS 2017)
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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/TNF alpha/IL beta 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/TNF alpha/IL beta-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/TNF alpha/IL beta 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.
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