Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth

Kellaway, S. G.; Potluri, S.; Keane, P.; Blair, H.; Chin, P. S.; Ptasinska, A.; Worker, A.; Ames, L.; Adamo, A.; Coleman, D. J.; Khan, N.; Assi, S.; Krippner-Heidenreich, A.; Raghavan, M.; Cockerill, P. N.; Heidenreich, O.; Bonifer, C.

doi:10.1101/2023.03.10.532081

bioRxiv · 10.1101/2023.03.10.532081

Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth

Kellaway, S. G.·Potluri, S.·Keane, P.·Blair, H.·Chin, P. S.·Ptasinska, A.·Worker, A.·Ames, L.·Adamo, A.·Coleman, D. J.·Khan, N.·Assi, S.·Krippner-Heidenreich, A.·Raghavan, M.·Cockerill, P. N.·Heidenreich, O.·Bonifer, C.

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Abstract

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re- grow remain unknown. Here, we examined the well characterised t(8;21) AML sub-type as a model to address this question. Using a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

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Kellaway, S. G., Potluri, S., Keane, P., Blair, H., Chin, P. S., Ptasinska, A., Worker, A., Ames, L., Adamo, A., Coleman, D. J., Khan, N., Assi, S., Krippner-Heidenreich, A., Raghavan, M., Cockerill, P. N., Heidenreich, O., Bonifer, C.. 2023-03-12. Leukemic stem cells hijack lineage inappropriate signalling pathways to promote their growth. https://doi.org/10.1101/2023.03.10.532081

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