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NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species.

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 (1-3). However, mechanisms that regulate the amount of ROS in leukemia-initiating cells (LICs)... Full description

Journal Title: Nature medicine November 2012, Vol.18(11), pp.1693-1698
Main Author: Giambra, Vincenzo
Other Authors: Jenkins, Christopher R , Wang, Hongfang , Lam, Sonya H , Shevchuk, Olena O , Nemirovsky, Oksana , Wai, Carol , Gusscott, Sam , Chiang, Mark Y , Aster, Jon C , Humphries, R Keith , Eaves, Connie , Weng, Andrew P
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1546-170X ; DOI: 10.1038/nm.2960
Link: http://search.proquest.com/docview/1151032308/?pq-origsite=primo
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title: NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species.
format: Article
creator:
  • Giambra, Vincenzo
  • Jenkins, Christopher R
  • Wang, Hongfang
  • Lam, Sonya H
  • Shevchuk, Olena O
  • Nemirovsky, Oksana
  • Wai, Carol
  • Gusscott, Sam
  • Chiang, Mark Y
  • Aster, Jon C
  • Humphries, R Keith
  • Eaves, Connie
  • Weng, Andrew P
subjects:
  • Animals–Metabolism
  • Cells, Cultured–Metabolism
  • Core Binding Factor Alpha 2 Subunit–Metabolism
  • Core Binding Factor Alpha 3 Subunit–Metabolism
  • Gene Expression Regulation, Leukemic–Pathology
  • Humans–Antagonists & Inhibitors
  • Jurkat Cells–Genetics
  • Leukocytes, Mononuclear–Metabolism
  • Mice–Metabolism
  • Mice, Knockout–Genetics
  • Molecular Targeted Therapy–Metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma–Metabolism
  • Protein Kinase C–Metabolism
  • Reactive Oxygen Species–Metabolism
  • Receptor, Notch1–Metabolism
  • Signal Transduction–Metabolism
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factor Alpha 3 Subunit
  • Notch1 Protein, Human
ispartof: Nature medicine, November 2012, Vol.18(11), pp.1693-1698
description: 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 (1-3). 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.sup.low] subset of [CD44.sup.+] 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[theta] (PKC-[theta]). Notably, primary mouse T-ALLs lacking PKC-[theta] show improved LIC activity, whereas enforced PKC-u expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC-[theta] is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC-[theta]. NOTCH1, which is frequently activated by mutation in T-ALL (4-6) and required for LIC activity in both mouse and human models (7), (8) thus acts to repress PKC-[theta]. These results reveal key functional roles for PKC-[theta] and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-[theta]expression or activity, or the accumulation of ROS.
language: eng
source:
identifier: E-ISSN: 1546-170X ; DOI: 10.1038/nm.2960
fulltext: fulltext
issn:
  • 1546170X
  • 1546-170X
url: Link


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titleNOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species.
creatorGiambra, Vincenzo ; Jenkins, Christopher R ; Wang, Hongfang ; Lam, Sonya H ; Shevchuk, Olena O ; Nemirovsky, Oksana ; Wai, Carol ; Gusscott, Sam ; Chiang, Mark Y ; Aster, Jon C ; Humphries, R Keith ; Eaves, Connie ; Weng, Andrew P
contributorGiambra, Vincenzo (correspondence author) ; Giambra, Vincenzo (record owner)
ispartofNature medicine, November 2012, Vol.18(11), pp.1693-1698
identifierE-ISSN: 1546-170X ; DOI: 10.1038/nm.2960
subjectAnimals–Metabolism ; Cells, Cultured–Metabolism ; Core Binding Factor Alpha 2 Subunit–Metabolism ; Core Binding Factor Alpha 3 Subunit–Metabolism ; Gene Expression Regulation, Leukemic–Pathology ; Humans–Antagonists & Inhibitors ; Jurkat Cells–Genetics ; Leukocytes, Mononuclear–Metabolism ; Mice–Metabolism ; Mice, Knockout–Genetics ; Molecular Targeted Therapy–Metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma–Metabolism ; Protein Kinase C–Metabolism ; Reactive Oxygen Species–Metabolism ; Receptor, Notch1–Metabolism ; Signal Transduction–Metabolism ; Core Binding Factor Alpha 2 Subunit ; Core Binding Factor Alpha 3 Subunit ; Notch1 Protein, Human
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descriptionReactive 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 (1-3). 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.sup.low] subset of [CD44.sup.+] 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[theta] (PKC-[theta]). Notably, primary mouse T-ALLs lacking PKC-[theta] show improved LIC activity, whereas enforced PKC-u expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC-[theta] is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC-[theta]. NOTCH1, which is frequently activated by mutation in T-ALL (4-6) and required for LIC activity in both mouse and human models (7), (8) thus acts to repress PKC-[theta]. These results reveal key functional roles for PKC-[theta] and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-[theta]expression or activity, or the accumulation of ROS.
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titleNOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species.
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titleNOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-θ and reactive oxygen species.
authorGiambra, Vincenzo ; Jenkins, Christopher R ; Wang, Hongfang ; Lam, Sonya H ; Shevchuk, Olena O ; Nemirovsky, Oksana ; Wai, Carol ; Gusscott, Sam ; Chiang, Mark Y ; Aster, Jon C ; Humphries, R Keith ; Eaves, Connie ; Weng, Andrew P
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