Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

Autor: Ross A. Dickins, Benjamin T. Kile, Steven Ngo, Andrew C. Perkins, Mark D. McKenzie, Margherita Ghisi, Olivia Susanto, Michael J. Hickey, Helen Mitchell, Peter Kanellakis, Ethan P. Oxley, Maximilian M. Garwood
Rok vydání: 2021
Předmět:
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021)
Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-26849-w
Popis: Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.
Differentiation therapy induces the maturation and clearance of acute myeloid leukemia cells. Here, using a mouse model, the authors show that a specific lineage of mature leukemia-derived cells persists during remission and is responsible for disease relapse.
Databáze: OpenAIRE
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