The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112

Xinping Yang, Liyun Liu, David Sternberg, Liren Tang, Ilene Galinsky, Daniel DeAngelo, Richard Stone

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Internal tandem duplication (ITD) mutations in the FLT3 tyrosine kinase have been detected in ∼20% of acute myeloid leukemia (AML) patients. Patients harboring FLT3/ITD mutations have a relatively poor prognosis. FLT3/ITD results in constitutive autophosphorylation of the receptor and factor-independent survival. Previous studies have shown that FLT3/ ITD activates the signal transducers and activators of transcription 5 (STAT5), p42/p44 mitogen-activated protein kinase [MAPK; extracellular signal-regulated kinase (ERK) 1/2], and phosphatidylinositol 3-kinase/Akt pathways. We herein provide biochemical and biological evidence that ribosomal S6 kinase 1 (RSK1) and protein kinase A (PKA) are the two principal kinases that mediate the antiapoptotic function of FLT3/ITD via phosphorylation of BAD at Ser 112. Inhibiting both MAPK kinase (MEK)/ERK and PKA pathways by a combination of U0126 (10 μmol/L) and H-89 (5 μmol/L) reduced most of BAD phosphorylation at Ser112 and induced apoptosis to a level comparable with that induced by FLT3 inhibitor AG1296 (5 μmol/L) in BaF3/FLT3/ITD cells. RNA interference of RSK1 or PKA catalytic subunit reduced BAD phosphorylation and induced apoptosis. The MEK inhibitor U0126 and/or the PKA inhibitor H-89 greatly enhanced the efficacy of the FLT3 inhibitor AG1296, suggesting that combining FLT3/ITD downstream pathway inhibition with FLT3 inhibitors may be a viable therapeutic strategy for AML caused by a FLT3/ITD mutation.

Original languageEnglish
Pages (from-to)7338-7347
Number of pages10
JournalCancer Research
Volume65
Issue number16
DOIs
StatePublished - 15 Aug 2005

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