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dc.contributor.authorGiambra, Vincenzoen_US
dc.contributor.authorJenkins, Christopher R.en_US
dc.contributor.authorWang, Hongfangen_US
dc.contributor.authorLam, Sonya H.en_US
dc.contributor.authorShevchuk, Olena O.en_US
dc.contributor.authorNemirovsky, Oksanaen_US
dc.contributor.authorWai, Carolen_US
dc.contributor.authorGusscott, Samen_US
dc.contributor.authorChiang, Mark Y.en_US
dc.contributor.authorAster, Jon C.en_US
dc.contributor.authorHumphries, R. Keithen_US
dc.contributor.authorEaves, Connieen_US
dc.contributor.authorWeng, Andrew P.en_US
dc.date.accessioned2014-03-01T02:24:51Z
dc.date.issued2013en_US
dc.identifier.citationGiambra, V., C. R. Jenkins, H. Wang, S. H. Lam, O. O. Shevchuk, O. Nemirovsky, C. Wai, et al. 2013. “PKCθ Regulates T-Cell Leukemia-Initiating Activity via Reactive Oxygen Species.” Nature medicine 18 (11): 1693-1698. doi:10.1038/nm.2960. http://dx.doi.org/10.1038/nm.2960.en
dc.identifier.issn1078-8956en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11855820
dc.description.abstractReactive oxygen species (ROS), a by-product of cellular metabolism, damage intracellular macromolecules and, in excess, can promote normal hematopoietic stem cell differentiation and exhaustion1–3. However, mechanisms that regulate ROS levels in leukemia-initiating cells (LICs) and the biological role of ROS in these cells remain largely unknown. We show here the ROSlow subset of CD44+ cells in T-cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T-cell progenitors, to be highly enriched in the most aggressive LICs, and that ROS are maintained at low levels by downregulation of protein kinase C theta (PKCθ). Strikingly, primary mouse T-ALLs lacking PKCθ show improved LIC activity whereas enforced PKCθ expression in both mouse and human primary T-ALLs compromised LIC activity. We also demonstrate that PKCθ is positively regulated by RUNX1, and that NOTCH1, which is frequently activated by mutation in T-ALL4–6 and required for LIC activity in both mouse and human models7,8, downregulates PKCθ and ROS via a novel pathway involving induction of RUNX3 and subsequent repression of RUNX1. These results reveal key functional roles for PKCθ and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKCθ expression/activity or ROS accumulation.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/nm.2960en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738873/pdf/en
dash.licenseLAAen_US
dc.titlePKCθ Regulates T-Cell Leukemia-Initiating Activity via Reactive Oxygen Speciesen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalNature medicineen
dash.depositing.authorWang, Hongfangen_US
dc.date.available2014-03-01T02:24:51Z
dc.identifier.doi10.1038/nm.2960*
dash.authorsorderedfalse
dash.contributor.affiliatedWang, Hongfang
dash.contributor.affiliatedAster, Jon


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