Pro‐inflammatory cytokines favor the emergence of ETV6‐RUNX1‐positive pre‐leukemic cells in a model of mesenchymal niche
Linda Beneforti, Erica Dander, Silvia Bresolin, Clara Bueno, Denise Acunzo, Mayla Bertagna, Anthony M. Ford, Bernhard Gentner, Geertruy te Kronnie, Patrizia Vergani, Pablo Menéndez, Andrea Biondi, Giovanna D’Amico, Chiara Palmi, Giovanni Cazzaniga
Abstract
Summary 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.