B-Cell Precursor Acute Lymphoblastic Leukemia elicits an Interferon-α/β response in Bone Marrow-derived Mesenchymal Stroma.

Smeets, M. W. E.; Steeghs, E. M. P.; Orsel, J.; Stalpers, F.; Vermeeren, M. M. P.; Veltman, C. H. J.; Nierkens, S.; van de Ven, C.; den Boer, M. L.

doi:10.1101/2023.05.09.539232

bioRxiv · 10.1101/2023.05.09.539232

B-Cell Precursor Acute Lymphoblastic Leukemia elicits an Interferon-α/β response in Bone Marrow-derived Mesenchymal Stroma.

Smeets, M. W. E.·Steeghs, E. M. P.·Orsel, J.·Stalpers, F.·Vermeeren, M. M. P.·Veltman, C. H. J.·Nierkens, S.·van de Ven, C.·den Boer, M. L.

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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 (MSCs) 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-sorted MSCs after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSCs, which was partially dependent on cell-cell signaling by tunneling nanotubes. The signature was selectively induced by BCP-ALL cells, most profoundly by ETV6-RUNX1 positive ALL cells, as co-culture of MSCs with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSCs both secreted IFN and IFN{beta}, but no IFN{gamma}. In line, the IFN-gene signature was sensitive to blockade of IFN/{beta} signaling, but less to that of IFN{gamma}. The viability of leukemic cells and level of resistance to three chemotherapeutic agents was not affected by interference with IFN signaling using selective IFN/{beta} inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFN/{beta}-related genes by MSCs does not support survival of BCP-ALL cells but may serve a different role in the pathobiology of BCP-ALL.

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Smeets, M. W. E., Steeghs, E. M. P., Orsel, J., Stalpers, F., Vermeeren, M. M. P., Veltman, C. H. J., Nierkens, S., van de Ven, C., den Boer, M. L.. 2023-05-10. B-Cell Precursor Acute Lymphoblastic Leukemia elicits an Interferon-α/β response in Bone Marrow-derived Mesenchymal Stroma.. https://doi.org/10.1101/2023.05.09.539232

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