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

TY - JOUR

T1 - Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion

AU - Cornils, Kerstin

AU - Thielecke, Lars

AU - Winkelmann, Doreen

AU - Aranyossy, Tim

AU - Lesche, Mathias

AU - Dahl, Andreas

AU - Roeder, Ingo

AU - Fehse, Boris

AU - Glauche, Ingmar

PY - 2017/7/14

Y1 - 2017/7/14

N2 - BACKGROUND: Clonal 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.METHODS: We 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.RESULTS: While 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.CONCLUSION: Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context.

AB - BACKGROUND: Clonal 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.METHODS: We 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.RESULTS: While 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.CONCLUSION: Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context.

KW - Journal Article

U2 - 10.1186/s12943-017-0668-x

DO - 10.1186/s12943-017-0668-x

M3 - SCORING: Journal article

C2 - 28709463

VL - 16

SP - 120

JO - MOL CANCER

JF - MOL CANCER

SN - 1476-4598

IS - 1

ER -