Clonal Evolution Enhances Leukemia-Propagating Cell Frequency in T Cell Acute Lymphoblastic Leukemia through Akt/mTORC1 Pathway Activation

• Published in: Cancer cell Vol. 25; no. 3; pp. 366 - 378
• Main Authors: Blackburn, Jessica S., Liu, Sali, Wilder, Jayme L., Dobrinski, Kimberly P., Lobbardi, Riadh, Moore, Finola E., Martinez, Sarah A., Chen, Eleanor Y., Lee, Charles, Langenau, David M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2014
• Subjects: Animals; Animals, Genetically Modified; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis - genetics; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Clonal Evolution - genetics; Danio rerio; Dexamethasone - pharmacology; Disease Progression; Drug Resistance, Neoplasm; Enzyme Activation; Genetic Variation; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Mechanistic Target of Rapamycin Complex 1; Molecular Sequence Data; Multiprotein Complexes - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-myc - metabolism; T-Lymphocytes - cytology; T-Lymphocytes - pathology; TOR Serine-Threonine Kinases - metabolism; Zebrafish
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2014.01.032

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. [Display omitted] •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.