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

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/TNFa/ILb 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/TNFa/ILb-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/ TNFa/ILb compared to their normal counterparts. Finally, the extent of DNA damage increases within the inflamed niche in both control and E/Rexpressing Ba/F3, potentially leading to transformation in the apoptosis-resistant pre-leukemic clone. Overall, our data provide new mechanistic insights into childhood ALL pathogenesis.

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis

“…Our results uncover an essential mechanism involving the proinflammatory cytokine IL-6 in sustaining Pax5-dependent B-ALL development. Abnormal profiles of inflammatory markers, including higher concentrations of IL-6, IL-17, and IL-18, have already been detected in neonatal blood spot samples of children who later developed B-cell precursor ALL 34 , and in vitro studies have also shown that pro-inflammatory cytokines like IL-6/IL-1β/ TNFα 35 or TGF-β dependent signaling 36,37 , can predispose pre-leukemic B cells to malignant transformation. However, the real contribution of these inflammatory pathways to B-ALL development remains unclear.…”

Toward prevention of childhood ALL by early-life immune training

“… 26 Furthermore, bone marrow stroma cells in the presence of tumor necrosis factor-α/IL-6 and IL-1β supported the outgrowth of ETV6-RUNX1 + preleukemic clones in a hematopoietic niche model of ETV6-RUNX1 + Ba/F3 cells. 27 …”

Can we prevent childhood Leukaemia?

“…The model posits that these necessary secondary mutations are an indirect consequence of a dysregulated immune response or chronic inflammation consequent to common infections [ 7 ]. There is some mechanistic insight into how this might happen [ 21 , 22 ]. The infections involved are not identified, though respiratory viruses have been implicated [ 23 , 24 ].…”