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. 2020 Jul;190(2):262-273.
doi: 10.1111/bjh.16523. Epub 2020 Mar 2.

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

Linda Beneforti  1 , Erica Dander  1 , Silvia Bresolin  2 , Clara Bueno  3 , Denise Acunzo  1 , Mayla Bertagna  1 , Anthony Ford  4 , Bernhard Gentner  5 , Geertruy Te Kronnie  2 , Patrizia Vergani  6 , Pablo Menéndez  3   7   8 , Andrea Biondi  1   9 , Giovanna D'Amico  1 , Chiara Palmi  1 , Giovanni Cazzaniga  1
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Free article

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

Linda Beneforti et al. Br J Haematol. 2020 Jul.
Free article

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.

Keywords: ALL; ETV6-RUNX1; MSC; inflammation; pre-leukemia.

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