Inflammation favors the emergence of ETV6-RUNX1-positive pre-leukemic cells in a model of mesenchymal niche

ETV6-RUNX1 (E/R) fusion gene, arising in utero from t(12;21), is the most frequent alteration in childhood acute lymphoblastic leukemia (ALL). Despite this, E/R is insufficient to overt disease since it generates a clinically silent pre-leukemic clone which contributes to hematopoiesis but fail to out-compete normal hematopoietic progenitors. Conversely, pre-leukemic cells show increased susceptibility to malignant transformation following additional genetic insults. Infections/inflammation are the most accredited triggers for mutations accumulation and progression in E/R+ pre-leukemic cells. However, how E/R and inflammation interact in promoting leukemia, both directly or through other cellular components in the bone marrow (BM) niche, 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+ murine pro-B cells over their normal counterparts by differentially affecting their proliferation, survival and migration. Very interesting, E/R-expressing human CD34+IL7R+ progenitors, a candidate population for pre-leukemic initiation during development, were preserved within the inflamed niche compared to their normal counterparts. Finally, the extent of DNA damage and activation-induced cytidine deaminase (AID) expression increase within the inflamed niche in both cell type, potentially leading to transformation in the apoptosis-resistant pre-leukemic clone. Overall, our data provide new mechanistic insights in childhood ALL pathogenesis. Gene expression was measured on GeneChip Mouse 2.0 platform of cells derived from BaF3 cells with TEL_AML1 fusion trascript and from wild type BaF3 cells.