Page 13 - Haematologica Vol. 109 - July 2024

EDITORIAL A. Kumar and S. Swaminathan
Figure 1. Type I interferons in B-cell precursor acute lymphoblastic leukemia. Smeets et al. found that acute lymphoblastic leu- kemia (ALL) cells, primarily the ETV6-RUNX1+ subtype, induce the paracrine expression of type I interferons (IFN-I) and IFN-I-stim- ulated genes (ISG) in co-cultured bone marrow mesenchymal stromal cells (MSC). IFN-I pathway induction in MSC is partially mediated via direct contact between leukemia cells and MSC. Induction of ISG and IFN-I production from MSC has an indirect effect on the ALL. This indirect effect of MSC-derived IFN-I may be potentially mediated by non-malignant host immune cells.
is consistent with Dunn et al.’s seminal finding that only cells of the hematopoietic lineage mediate the anticancer effects of IFN-I. Dunn et al. made their discovery in a solid tumor model of fibrosarcoma that is very different from leukemia in which malignancy arises in the hematopoi- etic cells themselves.3 Studying the role of IFN-I in BCP ALL, we showed that IFN-I mediate their anti-leukemic effects indirectly by activating host immune defenses. We found that IFN-I enhance the production and maturation of the non-malignant, innate immune cytotoxic natural killer cells in the ALL microenvironment by stimulating the production of interleukin-15, the IFN-I-induced cy- tokine critical for natural killer-cell homeostasis.6 We found significantly higher expression of interleukin-15 in patients with ETV6-RUNX1+ BCP ALL than in higher risk ALL subgroups, suggesting more intact IFN-I-induced immune responses in the former.6 The work by Smeets
et al. thus complements ours by demonstrating that: (i) MSC-derived IFN-I mediate their effects on ALL indirect- ly; and (ii) ETV6-RUNX1+ BCP ALL have a distinctly higher IFN-I-driven immune response signature in comparison to other ALL subtypes (Figure 1).
The publication by Smeets and colleagues is topical and opens additional avenues for research. The ETV6-RUNX1 subgroup of BCP ALL is unique in terms of its clinical out- come and etiology. Children with this form of ALL have one of the most favorable clinical outcomes with event- free survival for these patients after standard therapies exceeding 90%.8 The increased IFN-I pathway signature in ETV6-RUNX1-driven BCP ALL as compared to other ALL subtypes and the heightened ability of ETV6-RUNX1+ ALL cells to induce ISG in surrounding MSC1 could explain the favorable clinical outcomes of patients with this form of ALL. Another interesting feature of ETV6-RUNX1+ BCP ALL
Haematologica | 109 July 2024
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