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

Caiado, F., Maia-Silva, D., Jardim, C., Schmolka, N., Carvalho, T., Reforco, C., Faria, R., Kolundzija, B., Simoes, A. E., Baubec, T., Vakoc, C. R., da Silva, M. G., Manz, M. G., Schumacher, T. N., Norell, H., Silva-Santos, B. (November 2019) Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection. Nat Commun, 10 (1). p. 4986. ISSN 2041-1723

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DOI: 10.1038/s41467-019-12983-z


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.

Item Type: Paper
Additional Information: Author Correction on 11/26/19: The original version of this Article omitted the following from the last sentence of the Acknowledgements: UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado. This has now been corrected in both the PDF and HTML versions of the Article.
Subjects: Investigative techniques and equipment > cell lineage tracing
diseases & disorders > cancer > drugs and therapies > chemotherapy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein methylation > histone methylation
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics and Genomics Program
CSHL labs > Vakoc lab
School of Biological Sciences > Publications
Depositing User: Matthew Dunn
Date: 1 November 2019
Date Deposited: 08 Nov 2019 16:29
Last Modified: 09 Sep 2021 18:23
PMCID: PMC6825213
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