title: NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species.
abstract: Reactive oxygen species (ROS), a byproduct of cellular metabolism, damage intracellular macromolecules and, when present in excess, can promote normal hematopoietic stem cell differentiation and exhaustion. However, mechanisms that regulate the amount of ROS in leukemia-initiating cells (LICs) and the biological role of ROS in these cells are largely unknown. We show here that the ROS(low) subset of CD44(+) cells in T cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T cell progenitors, is highly enriched in the most aggressive LICs and that ROS accumulation is restrained by downregulation of protein kinase C θ (PKC-θ). Notably, primary mouse T-ALLs lacking PKC-θ show improved LIC activity, whereas enforced PKC-θ expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC-θ is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC-θ. NOTCH1, which is frequently activated by mutation in T-ALL and required for LIC activity in both mouse and human models, thus acts to repress PKC-θ. These results reveal key functional roles for PKC-θ and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-θ expression or activity, or the accumulation of ROS.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Giambra
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jenkins
authors.forename: Hongfang
authors.initials: H
authors.lastname: Wang
authors.forename: Sonya H
authors.initials: SH
authors.lastname: Lam
authors.forename: Olena O
authors.initials: OO
authors.lastname: Shevchuk
authors.forename: Oksana
authors.initials: O
authors.lastname: Nemirovsky
authors.forename: Carol
authors.initials: C
authors.lastname: Wai
authors.forename: Sam
authors.initials: S
authors.lastname: Gusscott
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Chiang
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.forename: Connie
authors.initials: C
authors.lastname: Eaves
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; C497761:NOTCH1 protein, human; C493728:RUNX1 protein, human; D017382:Reactive Oxygen Species; D051881:Receptor, Notch1; C493729:Runx3 protein, human; D011493:Protein Kinase C