Clonal Evolution Enhances Leukemia-Propagating Cell Frequency in T Cell Acute Lymphoblastic Leukemia through Akt/mTORC1 Pathway Activation
Menée à l'aide de poissons zèbres transgéniques, cette étude met en évidence des mécanismes par lesquels, via l'activation de la signalisation Akt, certaines populations clonales de leucémie lymphoblastique aiguë T acquièrent spontanément, en l'absence d'une pression de sélection induite par un traitement, des caractéristiques de cellules souches et de résistance à une chimiothérapie
Clonal evolution and intratumoral heterogeneity drive cancer progression through unknown molecular mechanisms. To address this issue, functional differences between single T cell acute lymphoblastic leukemia (T-ALL) clones were assessed using a zebrafish transgenic model. Functional variation was observed within individual clones, with a minority of clones enhancing growth rate and leukemia-propagating potential with time. Akt pathway activation was acquired in a subset of these evolved clones, which increased the number of leukemia-propagating cells through activating mTORC1, elevated growth rate likely by stabilizing the Myc protein, and rendered cells resistant to dexamethasone, which was reversed by combined treatment with an Akt inhibitor. Thus, T-ALL clones spontaneously and continuously evolve to drive leukemia progression even in the absence of therapy-induced selection. "Spontaneous and continued clonal evolution occurs within single T-ALL cells "Clonal evolution enhances LPC frequency, growth, and therapy resistance "Clonal evolution can activate the Akt/mTORC1 pathway to increase LPC frequency "Akt inhibitors sensitize LPCs to dexamethasone-induced killing Blackburn et al. report that some T cell acute lymphoblastic leukemia clones spontaneously evolve to obtain enhanced growth rate, leukemia-propagating potential, and chemotherapy resistance in the absence of therapy-induced selection. They find this is sometimes achieved by acquiring Akt pathway activation.