title: Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation.
abstract: 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.
authors.affiliation: Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Blackburn
authors.affiliation: Northwestern University, Chicago, IL 60208, USA.
authors.forename: Sali
authors.initials: S
authors.lastname: Liu
authors.affiliation: Harvard Stem Cell Institute, Boston, MA 02138, USA.
authors.forename: Jayme L
authors.initials: JL
authors.lastname: Wilder
authors.affiliation: Center for Integrative Medicine, University of South Florida, Tampa, FL 33620, USA.
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Dobrinski
authors.affiliation: Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA.
authors.forename: Riadh
authors.initials: R
authors.lastname: Lobbardi
authors.affiliation: Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA.
authors.forename: Finola E
authors.initials: FE
authors.lastname: Moore
authors.affiliation: Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Martinez
authors.affiliation: Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA; Department of Pathology, University of Washington Medical Center, Seattle, WA 98195, USA.
authors.forename: Eleanor Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA; Department of Graduate Studies, Seoul National University School of Medicine, Seoul 110-744, South Korea.
authors.forename: Charles
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pathology, Regenerative Medicine and Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Boston, MA 02138, USA. Electronic address: dlangenau@mgh.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Langenau
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D014644:Genetic Variation; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D018931:Antineoplastic Agents, Hormonal; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; D003907:Dexamethasone; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases