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Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions.
Morita, Ken; Maeda, Shintaro; Suzuki, Kensho; Kiyose, Hiroki; Taniguchi, Junichi; Liu, Pu Paul; Sugiyama, Hiroshi; Adachi, Souichi; Kamikubo, Yasuhiko.
Afiliação
  • Morita K; Department of Human Health Sciences, Graduate School of Medicine, and.
  • Maeda S; Department of Human Health Sciences, Graduate School of Medicine, and.
  • Suzuki K; Department of Human Health Sciences, Graduate School of Medicine, and.
  • Kiyose H; Department of Human Health Sciences, Graduate School of Medicine, and.
  • Taniguchi J; Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan.
  • Liu PP; Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; and.
  • Sugiyama H; Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan.
  • Adachi S; Department of Human Health Sciences, Graduate School of Medicine, and.
  • Kamikubo Y; Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Blood Adv ; 1(18): 1440-1451, 2017 Aug 08.
Article em En | MEDLINE | ID: mdl-29296785
Besides being a classical tumor suppressor, runt-related transcription factor 1 (RUNX1) is now widely recognized for its oncogenic role in the development of acute myeloid leukemia (AML). Here we report that this bidirectional function of RUNX1 possibly arises from the total level of RUNX family expressions. Indeed, analysis of clinical data revealed that intermediate-level gene expression of RUNX1 marked the poorest-prognostic cohort in relation to AML patients with high- or low-level RUNX1 expressions. Through a series of RUNX1 knockdown experiments with various RUNX1 attenuation potentials, we found that moderate attenuation of RUNX1 contributed to the enhanced propagation of AML cells through accelerated cell-cycle progression, whereas profound RUNX1 depletion led to cell-cycle arrest and apoptosis. In these RUNX1-silenced tumors, amounts of compensative upregulation of RUNX2 and RUNX3 expressions were roughly equivalent and created an absolute elevation of total RUNX (RUNX1 + RUNX2 + RUNX3) expression levels in RUNX1 moderately attenuated AML cells. This elevation resulted in enhanced transactivation of glutathione S-transferase α 2 (GSTA2) expression, a vital enzyme handling the catabolization of intracellular reactive oxygen species (ROS) as well as advancing the cell-cycle progressions, and thus ultimately led to the acquisition of proliferative advantage in RUNX1 moderately attenuated AML cells. Besides, treatment with ethacrynic acid, which is known for its GSTA inhibiting property, actually prolonged the survival of AML mice in vivo. Collectively, our findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in antileukemia strategy.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2017 Tipo de documento: Article