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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226600 | GEO | 2024/01/06

REPOSITORIES: GEO

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Project description:Patients with acute myeloid leukaemia (AML) often achieve remission yet subsequently die of disease relapse, which is commonly driven by chemotherapy-resistant leukaemic stem cells (LSCs). LSCs are defined by their capacity to initiate leukaemia in immuno-compromised mice. This precludes an analysis of their interaction with lymphocytes as components of anti-tumour immunity, which LSCs must escape in order to induce cancer7. Here we propose that stemness and immune evasion are closely intertwined in human AML. Using human AML xenograft and syngeneic mouse leukemia models, we show that ligands of the danger detector NKG2D, a critical mediator of anti-tumour immunity by cytotoxic lymphocytes such as natural killer (NK) cells, are generally expressed on bulk AML cells but not on LSCs. Functional LSCs can be isolated by their lack of NKG2D ligand (NKG2DL) expression, even in human AMLs not expressing the conventional LSC marker CD34. NKG2DL expressing AML cells are cleared by NK cells while NKG2DLneg leukaemic cells isolated from the same individuals escape NK cell killing. These NKG2DLneg AML cells show an immature morphology, display molecular and functional stemness characteristics, can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplants (PDX). Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) negatively regulates NKG2DL and PARP1 inhibition (PARPi) induces NKG2DL surface expression in LSCs. Consequently, co-treatment with PARPi and NK cells suppresses leukaemogenesis in PDX models. Low expression of surface NKG2DL as well as high PARP1 expression are associated with inferior clinical outcome in patients with AML. In summary, our data link the concept of LSCs to immune escape and indicate absence of immunostimulatory NKG2DL as a novel method to identify LSCs across genetic AML subtypes. Moreover, we provide a strong rationale for targeting therapy resistant LSCs by PARP1 inhibition rendering them amenable to NK cell control in vivo.

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

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