3122 – DYNAMIC REGULATION OF HIERARCHICAL HETEROGENEITY IN ACUTE MYELOID LEUKAEMIA, SERVES AS A TUMOUR IMMUNOEVASION MECHANISM
| Autor: | Chrysi Christodoulidou, Maria-Nefeli Skoufou-Papoutsaki, Thomas N. Williams, Cristina Lo Celso, Shayin Gibson, Ronjon Chakraverty, Hans J. Stauss, Georgia Stevens, Francesca Hearn-Yeates, Sara Gonzalez-anton, Jack Hopkins, Reema Khorshed, Constandina Pospori, Dimitrios Stampoulis, Christiana Georgiou, Myriam L. R. Haltalli, Katherine Sloan, William Grey, Dominique Bonnet, Flora Birch |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
education.field_of_study Myeloid Mechanism (biology) T cell Population Inflammation Cell Biology Hematology Disease Biology medicine.anatomical_structure Downregulation and upregulation hemic and lymphatic diseases Genetics medicine Cancer research medicine.symptom Stem cell education Molecular Biology |
| Zdroj: | Experimental Hematology. 88:S75 |
| ISSN: | 0301-472X |
| DOI: | 10.1016/j.exphem.2020.09.131 |
| Popis: | Acute Myeloid Leukaemia (AML), is a haematological malignancy composed of hierarchically heterogeneous blasts. While leukaemic stem cells are known to initiate disease and drive relapse and progenitor-like populations form the bulk of the disease, less is known about the contribution of differentiated myeloid blasts to disease progression. Furthermore, the impact of inflammation, generated by endogenous or therapeutic anti-tumour T cell responses, on the hierarchical heterogeneity in AML has not been studied extensively. In this study, we set to investigate these questions. Using the well-established in vivo model of MLL-AF9-driven, murine AML, we combined the phenotypic analysis of AML blasts in the course of disease, with proliferation dynamics and fate-mapping experiments to demonstrate the presence of a terminally differentiated, chemoresistant blast population expressing high levels of PDL1. While this population lacked any leukaemia propagating capacity, it appeared to play a critical accessory role in facilitating disease progression in the presence of anti-tumour T cell responses. Importantly, IFNγ, secreted by anti-tumour T cells responding to leukaemic cells, induced AML blast differentiation coupled with PDL1 upregulation. Finally, we were able to show that a population-level plasticity in hierarchical and functional heterogeneity, allows the disease to dynamically adapt to microenvironmental changes, achieving a balance between tumour immunoevasion and growth, which ultimately facilitates disease progression. |
| Databáze: | OpenAIRE |
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