title: Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency.
abstract: NOTCH1 pathway activation contributes to the pathogenesis of over 60% of T-cell acute lymphoblastic leukemia (T-ALL). While Notch is thought to exert the majority of its effects through transcriptional activation of Myc, it also likely has independent roles in T-ALL malignancy. Here, we utilized a zebrafish transgenic model of T-ALL, where Notch does not induce Myc transcription, to identify a novel Notch gene expression signature that is also found in human T-ALL and is regulated independently of Myc. Cross-species microarray comparisons between zebrafish and mammalian disease identified a common T-ALL gene signature, suggesting that conserved genetic pathways underlie T-ALL development. Functionally, Notch expression induced a significant expansion of pre-leukemic clones; however, a majority of these clones were not fully transformed and could not induce leukemia when transplanted into recipient animals. Limiting-dilution cell transplantation revealed that Notch signaling does not increase the overall frequency of leukemia-propagating cells (LPCs), either alone or in collaboration with Myc. Taken together, these data indicate that a primary role of Notch signaling in T-ALL is to expand a population of pre-malignant thymocytes, of which a subset acquire the necessary mutations to become fully transformed LPCs.
authors.affiliation: Department of Pathology, Molecular Pathology Unit, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Blackburn
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: D M
authors.initials: DM
authors.lastname: Raiser
authors.forename: S A
authors.initials: SA
authors.lastname: Martinez
authors.forename: H
authors.initials: H
authors.lastname: Feng
authors.forename: N D
authors.initials: ND
authors.lastname: Meeker
authors.forename: J
authors.initials: J
authors.lastname: Gentry
authors.forename: D
authors.initials: D
authors.lastname: Neuberg
authors.forename: A T
authors.initials: AT
authors.lastname: Look
authors.forename: S
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: A
authors.initials: A
authors.lastname: Bernards
authors.forename: N S
authors.initials: NS
authors.lastname: Trede
authors.forename: D M
authors.initials: DM
authors.lastname: Langenau
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D060168:Thymocytes; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051881:Receptor, Notch1