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.

Details

Title
Lineage tracing of acute myeloid leukemia reveals the impact of hypomethylating agents on chemoresistance selection
Author
Caiado, Francisco 1   VIAFID ORCID Logo  ; Maia-Silva, Diogo 2   VIAFID ORCID Logo  ; Jardim, Carolina 1 ; Schmolka, Nina 3   VIAFID ORCID Logo  ; Carvalho, Tânia 1 ; Reforço, Cláudia 1   VIAFID ORCID Logo  ; Faria, Rita 1   VIAFID ORCID Logo  ; Kolundzija, Branka 1 ; Simões, André E 1 ; Baubec, Tuncay 4   VIAFID ORCID Logo  ; Vakoc, Christopher R 5 ; Gomes da Silva, Maria 6 ; Manz, Markus G 7   VIAFID ORCID Logo  ; Schumacher, Ton N 8   VIAFID ORCID Logo  ; Norell, Håkan 1 ; Silva-Santos, Bruno 1   VIAFID ORCID Logo 

 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal 
 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA 
 Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland 
 Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland 
 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA 
 Instituto Portugues de Oncologia—Francisco Gentil, Lisbon, Portugal 
 Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zürich, Switzerland 
 Netherlands Cancer Institute, Amsterdam, The Netherlands 
Pages
1-15
Publication year
2019
Publication date
Nov 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2311223008
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.