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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

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; ² Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts; ³ Division of Hermatology/Oncology, Mount Sinai School of Medicine, New York, New York; and ⁴ Department of Medicine, University of British Columbia, Vancouver Hospital, Vancouver, British Columbia, Canada

Requests for reprints: Richard Stone, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: 617-632-2214; Fax: 617-632-2933; E-mail: rstone{at}partners.org.

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 Ser¹¹². 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.

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