Survival of acute myeloid leukemia cells requires PI3 kinase activation

Qing Xu, Serge Emile Simpson, Timothy J. Scialla, Adam Bagg, Martin Carroll

Research output: Contribution to journalArticle

392 Citations (Scopus)

Abstract

The mechanisms that regulate the growth and survival of acute myeloid leukemia (AML) cells are largely unknown. We hypothesized that constitutive activation of phosphatidyl-inositide 3 kinase (PI3 kinase) could regulate survival in primary cells from patients with AML. Here we demonstrate that Akt, a critical substrate of PI3 kinase, is activated in AML blasts. In a short-term culture system, most AML patient samples showed a dose-dependent decrease in survival after incubation with the PI3 kinase inhibitor LY294002. This decrease in survival was partially due to the induction of apoptosis. Furthermore, we have shown that p70 S6 kinase and 4EBP-1, downstream mediators of Akt signaling, also are phosphorylated in AML blasts. Phosphorylation of these proteins is inhibited by the mTOR inhibitor RAD001. Incubation of AML blasts with RAD001 induces only a small decrease in survival of the cells; however, when combined with Ara-C, RAD001 enhances the toxicity of Ara-C. These results demonstrate that constitutive activation of the PI3 kinase pathway is necessary for the survival of AML blasts and that targeting of this pathway with pharmacologic inhibitors may be of clinical benefit in treatment of AML.

Original languageEnglish
Pages (from-to)972-980
Number of pages9
JournalBlood
Volume102
Issue number3
DOIs
StatePublished - Aug 1 2003

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Myeloid Cells
Acute Myeloid Leukemia
Phosphotransferases
Chemical activation
Cytarabine
70-kDa Ribosomal Protein S6 Kinases
Phosphorylation
Survival
Toxicity
Cells
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Substrates
Everolimus
Cell Survival
Proteins
Growth

ASJC Scopus subject areas

  • Hematology

Cite this

Xu, Q., Simpson, S. E., Scialla, T. J., Bagg, A., & Carroll, M. (2003). Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood, 102(3), 972-980. https://doi.org/10.1182/blood-2002-11-3429

Survival of acute myeloid leukemia cells requires PI3 kinase activation. / Xu, Qing; Simpson, Serge Emile; Scialla, Timothy J.; Bagg, Adam; Carroll, Martin.

In: Blood, Vol. 102, No. 3, 01.08.2003, p. 972-980.

Research output: Contribution to journalArticle

Xu, Q, Simpson, SE, Scialla, TJ, Bagg, A & Carroll, M 2003, 'Survival of acute myeloid leukemia cells requires PI3 kinase activation', Blood, vol. 102, no. 3, pp. 972-980. https://doi.org/10.1182/blood-2002-11-3429
Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003 Aug 1;102(3):972-980. https://doi.org/10.1182/blood-2002-11-3429
Xu, Qing ; Simpson, Serge Emile ; Scialla, Timothy J. ; Bagg, Adam ; Carroll, Martin. / Survival of acute myeloid leukemia cells requires PI3 kinase activation. In: Blood. 2003 ; Vol. 102, No. 3. pp. 972-980.
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