Page 12 - Haematologica Vol. 109 - July 2024

EDITORIAL
Type I interferons: leukemia’s old foe in the limelight again
Anil Kumar1 and Srividya Swaminathan1-3
1Department of Systems Biology, 2Department of Pediatrics and 3Department of Hematologic Malignancies, Beckman Research Institute of City of Hope, Duarte, CA, USA
In this issue of Haematologica, Smeets et al.1 shed new light on the regulation of the classical immunomodulatory cytokine family, type I interferons (IFN-I), in the ETV6-RUNX1 subgroup of acute lymphoblastic leukemia (ALL). Discovered in 1957 by Isaacs and Lindenmann, IFN-I gained prominence as critical regulators of antiviral innate immune respons- es. IFN-I production in response to viral infection or DNA damage induces the expression of IFN-stimulated genes (ISG). These ISG mediate the anti-proliferative, pro-apop- totic, and pro-inflammatory functions of IFN-I, a process that ultimately results in the elimination of the infected and/or damaged cells either directly or by host immune cells.2 Immune responses in cancers mimic those seen during viral infections.2 Consistent with this, Dunn and colleagues made the landmark discovery that IFN-I restrict solid tumorigenesis by activating both innate and adaptive arms of anticancer host immune defenses.3 IFN-I are thus widely regarded as ‘anticancer’ cytokines.
IFN-α2, a member of the IFN-I family, was the first immu- notherapeutic agent to be approved by the US Food and Drug Administration in 1986 for the treatment of hairy cell leukemia.4 The remarkable response rates observed in patients with hairy cell leukemia led to the expanded use of this cytokine in the treatment of other hematopoietic malignancies, including ALL.5 In ALL, IFN-I were shown to increase relapse-free survival in patients who received an allogeneic bone marrow hematopoietic stem cell trans- plant.5 Despite the remarkable improvements in clinical outcomes of patients treated with IFN-I, IFN-I gradually lost their charm as ‘wonder drugs’ due to off-target toxicity associated with their administration.2 Nevertheless, their strong anticancer function could never be refuted. IFN-I were unfortunately used in clinics at a time when their mode of therapeutic action was not completely understood. However, recently identified mechanisms of action of IFN-I in human ALL by Smeets et al.1 and us6 rekindle the interest of the scientific community in harnessing the therapeutic
potential of this age-old cytokine family in treating ALL. In 2005, Einav et al.7 discovered that patients with the most common and treatable form of childhood B-cell precursor (BCP) ALL, the ETV6-RUNX1+ subtype, were approximately three times more likely to exhibit an enhanced expression of ISG in comparison to children with high-risk BCP ALL subtypes such as those with MLL, E2A-PBX1, or BCR-ABL1 rearrangements and hypodiploidy. However, they did not delve into why ETV6-RUNX1 BCP ALL were associated with interferonopathy, which cells in the leukemia microenvi- ronment cause such interferonopathy, and which class(es) of IFN were induced.
In the current issue of Haematologica, Smeets et al.1 answer some questions arising from the publication by Einav and colleagues.7 They found that in pediatric patients with BCP ALL, bone marrow mesenchymal stromal cells (MSC) are a critical source of interferons, specifically the IFN-I α and b. Among childhood BCP ALL subtypes, they found that ETV6- RUNX1+ ALL most profoundly induces ISG in co-cultured bone marrow MSC derived from healthy donors and from children with ETV6-RUNX1+ and other ALL (hyperdiploid and those with DUX4, CRLF2, and EPOR translocations). They show that induction of ISG in MSC co-cultured with ETV6- RUNX1+ ALL cells occurs partly by direct contact between leukemic cells and MSC via tunneling nanotubes (Figure 1). Overall, the findings of Smeets and colleagues suggest that ETV6-RUNX1 could be a direct inducer of the IFN-I pathway in normal and ALL patient-derived MSC. Mecha- nistically how expression of ETV6-RUNX1 in leukemic blasts triggers the IFN-I signature in surrounding non-malignant MSC remains to be delineated. Together, the studies by Einav et al. and Smeets et al. raise interest in studying these biological mechanism(s).
Smeets and colleagues also observed that IFN-I from MSC co-cultured with ETV6-RUNX1+ BCP ALL cells do not directly impact the viability of the leukemic cells or their sensitivity to chemotherapeutic agents.1 This observation
Haematologica | 109 July 2024
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Correspondence: S. Swaminathan sswaminathan@coh.org
Received: Accepted: Early view:
March 1, 2024. March 14, 2024. March 21, 2024.
https://doi.org/10.3324/haematol.2024.285079
©2024 Ferrata Storti Foundation Published under a CC BY-NC license