Leukemic stem cells hijack lineage inappropriate signalling pathways to promote growth [scRNA-seq]

Acute Myeloid Leukemia (AML) is caused by different mutations which affect growth and differentiation of myeloid cells. Depending on the mutation sub-type, cells adopt different gene regulatory networks 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 cells (leukemic stem cells or LSCs) which escape chemotherapy and can emerge from quiescence to trigger a relapse. The signalling processes that allow such cells to re-grow remain unknown. Here, we examined the well characterised t(8;21) AML sub-type as model to address this question. We show that t(8;21) LSCs aberrantly activate the ectopic VEGF and IL-5 signalling pathways. We uncovered a regulatory circuit consisting of the driver oncoprotein RUNX1-ETO and the AP-1 / GATA2 transcription factor axis allowing LSCs to re-enter the cell cycle. Single-cell RNA sequencing of sorted leukemic stem cell and blast populations from t(8;21) AML patients pooled to form a single library