Dynamic regulation of hierarchical heterogeneity in Acute Myeloid Leukemia serves as a tumor immunoevasion mechanism
Pospori, C.; Grey, W.; Gonzalez-Anton, S.; Gibson, S. V.; Georgiou, C.; Birch, F.; Stevens, G.; Williams, T.; Khorshed, R.; Haltalli, M. L. R.; Skoufou-Papoutsaki, M.-N.; Sloan, K.; Encabo, H. H.; Hopkins, J.; Christodoulidou, C.; Stampoulis, D.; Hearn-Yates, F.; Gribben, J.; Stauss, H. J.; Chakraverty, R.; Bonnet, D.; Lo Celso, C. L.
Show abstract
Acute Myeloid Leukemia, a hematological malignancy with poor clinical outcome, is composed of hierarchically heterogeneous cells. We examine the contribution of this heterogeneity to disease progression in the context of anti-tumor immune responses and investigate whether these responses regulate the balance between stemness and differentiation in AML. Combining phenotypic analysis with proliferation dynamics and fate-mapping of AML cells in a murine AML model, we demonstrate the presence of a terminally differentiated, chemoresistant population expressing high levels of PDL1. We show that PDL1 upregulation in AML cells, following exposure to IFN{gamma} from activated T cells, is coupled with AML differentiation and the dynamic balance between proliferation, versus differentiation and immunosuppression, facilitates disease progression in the presence of immune responses. This microenvironment-responsive hierarchical heterogeneity in AML may be key in facilitating disease growth at the population level at multiple stages of disease, including following bone marrow transplantation and immunotherapy.
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