Page 59 - Haematologica Vol. 109 - July 2024

ARTICLE - Acute Lymphoblastic Leukemia
B-cell precursor acute lymphoblastic leukemia elicits an interferon-α/b response in bone marrow-derived mesenchymal stroma
Mandy W. E. Smeets,1,2* Elisabeth M. P. Steeghs,1* Jan Orsel,2 Femke Stalpers,2 Myrthe M. P. Vermeeren,2 Christina H. J. Veltman,2 Lotte Slenders,2 Stefan Nierkens,2,3 Cesca van de Ven2 and Monique L. den Boer1,2
1Department of Pediatrics, Erasmus MC-Sophia, Rotterdam; 2Princess Máxima Center for Pediatric Oncology, Utrecht and 3Center for Translational Immunology, University Medical Center, Utrecht, the Netherlands
*MWES and EMPS contributed equally as first authors.
Abstract
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSC) mimic this protective environment in ex vivo co-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flow-sort- ed MSC after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSC, which was partially dependent on direct cell-cell signaling. The signature was selectively induced by BCP-ALL cells, most profoundly by ETV6-RUNX1-positive ALL cells, as co-culture of MSC with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSC both secreted IFNα and IFNb, but not IFNγ. In line, the IFN gene signature was sensitive to blockade of IFNα/b signaling, but less to that of IFNγ. The viability of leukemic cells and level of resistance to three che- motherapeutic agents was not affected by interference with IFN signaling using selective IFNα/b inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFNα/b-related genes by MSC does not support survival of BCP-ALL cells but may serve a different role in the pathobiology of BCP-ALL.
Introduction
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common pediatric malignancy, and is character- ized by malignant transformation and clonal expansion of B-precursor cells in the bone marrow.1-3 The 5-year event-free survival rate of pediatric patients with BCP-ALL is currently ~90%.4-8 However, despite a relatively high cure rate, BCP-ALL still represents a major cause of cancer-related mortality in children, which can be attributed to treatment-related death or relapse of the leukemia.6,9
Several studies have shown that the bone marrow micro- environment facilitates leukemogenesis and contributes to cellular drug resistance.9-15 Bone marrow-derived mes- enchymal stromal cells (MSC) are a major component of the bone marrow microenvironment.16 Ex vivo, these cells provide a survival benefit to co-cultured leukemic cells and induce resistance to chemotherapeutic drugs. We previ- ously showed that leukemic cells become re-sensitized to
chemotherapeutics ex vivo when the interaction with MSC is disrupted, e.g., by interfering with tunneling nanotube formation.10 Leukemic cells use tunneling nanotubes as an effective mechanism to communicate with MSC. Transfer of mitochondria, autophagosomes, and transmembrane proteins towards MSC has been established.14 Disruption of tunneling nanotubes resulted in an altered profile of cyto- kines secreted by MSC and a reduced survival benefit for leukemic cells.10,14 These findings indicate that MSC play an important role in the maintenance of BCP-ALL, although the mechanism is yet unknown. To elucidate potential mecha- nisms, we investigated the effect of leukemic cells on the gene expression profile of MSC. Subsequently, we studied whether differentially expressed genes contributed to the viability and drug responsiveness of BCP-ALL. Our study shows that the interferon (IFN) α/b pathway is selectively activated in MSC upon interaction with BCP-ALL cells but not with normal, healthy immune cells. However, interference with this pathway did not affect either the viability or the
Haematologica | 109 July 2024
2073
Correspondence: M.L. den Boer m.l.denboer@prinsesmaximacentrum.nl
Received: Accepted: Early view:
May 13, 2023. February 15, 2024. February 29, 2024.
https://doi.org/10.3324/haematol.2023.283494
©2024 Ferrata Storti Foundation Published under a CC BY-NC license