Blackburn, Jessica S.Liu, SaliRaiser, DaveMartinez, Sarah A.Feng, HuiMeeker, Nathan D.Gentry, JefferyNeuberg, DonnaLook, A.Ramaswamy, SridharBernards, AndreTrede, Nikolaus S.Langenau, David2013-05-012012Blackburn, Jessica S., Sali Liu, David M. Raiser, Sarah A. Martinez, Hui Feng, Nathan D. Meeker, Jeffery Gentry, et al. 2012. Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. Leukemia 26(9): 2069-2078.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:10609670NOTCH1 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.en-USthymocyterelapseMyczebrafishself-renewalJournal Article2013-05-0110.1038/leu.2012.116