Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion

Molecular Cancer

Research

Andreas Dahl¹  Mathias Lesche¹  Ingo Roeder²  Lars Thielecke²  Ingmar Glauche²  Tim Aranyossy³  Doreen Winkelmann³  Boris Fehse³  Kerstin Cornils⁴ 

[1] Deep Sequencing Group SFB 655, Biotechnology Center, Technische Universität Dresden, Dresden, Germany;Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany;Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Present Adress: University Medical Center Hamburg-Eppendorf, Pediatric Hematology and Oncology & Research Institute Children’s Cancer Center Hamburg, Martinistr. 52, 20246, Hamburg, Germany;

关键词: BcrAbl;    Genetic barcodes;    Leukemia;    Heterogeneity;    Clonal dynamics;    Mathematical modelling;    Clonal competition;   

DOI  :  10.1186/s12943-017-0668-x

 received in 2017-04-25, accepted in 2017-05-25,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundClonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed.MethodsWe studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a γ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice.ResultsWhile we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones.ConclusionOur findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context.

【 授权许可】

CC BY   
© The Author(s). 2017