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

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0668-x) contains supplementary material, which is available to authorized users.

DNA Barcoding Reveals Habitual Clonal Dominance of Myeloma Plasma Cells in the Bone Marrow Microenvironment

“…Cellular DNA “barcoding” and deep sequencing [18] have been previously combined to examine lineage differentiation of hematopoietic stem cells/progenitors [19] , [20] and mammary epithelial cells [21] in vivo , and to track the clonal origins of hepatocyte and Bcr-Abl leukemia cell engraftment [22] , [23] and Cbx7-induced leukemias [24] . In the present study, we used functionally neutral, heritable DNA tags to uniquely label each myeloma PC.…”