Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection

Francisco Caiado (), Diogo Maia-Silva, Carolina Jardim, Nina Schmolka, Tânia Carvalho, Cláudia Reforço, Rita Faria, Branka Kolundzija, André E. Simões, Tuncay Baubec, Christopher R. Vakoc, Maria Gomes Silva, Markus G. Manz, Ton N. Schumacher, Håkan Norell () and Bruno Silva-Santos ()
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Francisco Caiado: Universidade de Lisboa
Diogo Maia-Silva: Universidade de Lisboa
Carolina Jardim: Universidade de Lisboa
Nina Schmolka: Universidade de Lisboa
Tânia Carvalho: Universidade de Lisboa
Cláudia Reforço: Universidade de Lisboa
Rita Faria: Universidade de Lisboa
Branka Kolundzija: Universidade de Lisboa
André E. Simões: Universidade de Lisboa
Tuncay Baubec: University of Zurich
Christopher R. Vakoc: Cold Spring Harbor
Maria Gomes Silva: Instituto Portugues de Oncologia—Francisco Gentil
Markus G. Manz: University Hospital Zurich and University of Zurich
Ton N. Schumacher: Netherlands Cancer Institute
Håkan Norell: Universidade de Lisboa
Bruno Silva-Santos: Universidade de Lisboa

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses. Mechanistically, DNMTi suppresses the outgrowth of a pre-determined set of chemoresistant AML clones with stemness properties, instead favoring the expansion of rarer and unfit chemosensitive clones. Importantly, we confirm the capacity of DNMTi combination to suppress stemness-dependent chemoresistance development in xenotransplantation models and primary AML patient samples. Together, these results support the potential of DNMTi combination treatment to circumvent the development of chemorefractory AML relapses.

Date: 2019
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DOI: 10.1038/s41467-019-12983-z

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