FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27 Kip1 in acute myeloid leukemia

• Published in: Haematologica (Roma) Vol. 102; no. 8; pp. 1378 - 1389
• Main Authors: Peschel, Ines, Podmirseg, Silvio R., Taschler, Martin, Duyster, Justus, Götze, Katharina S., Sill, Heinz, Nachbaur, David, Jäkel, Heidelinde, Hengst, Ludger
• Format: Journal Article
• Language: English
• Published: Italy 01.08.2017
• Subjects: Cell Cycle Checkpoints; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; fms-Like Tyrosine Kinase 3 - metabolism; Humans; Leukemia, Myeloid, Acute - metabolism; Phosphorylation; Protein Kinase Inhibitors - metabolism; Tandem Repeat Sequences; Tumor Cells, Cultured; Tyrosine - metabolism
• DOI: 10.3324/haematol.2016.160101
• ISSN: 0390-6078

P27 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. We observed that FLT3 and FLT3-ITD can directly bind and selectively phosphorylate p27 on this residue. Inhibition of FLT3-ITD in cell lines strongly reduced p27 tyrosine 88 phosphorylation and resulted in increased p27 levels and cell cycle arrest. Subsequent analysis revealed the presence of tyrosine 88 phosphorylated p27 in primary patient samples. Inhibition of FLT3 kinase activity with AC220 significantly reduced p27 tyrosine 88 phosphorylation in cells isolated from FLT3 wild type expressing acute myeloid leukemia (AML) patients. In FLT3-ITD positive AML patients, p27 tyrosine 88 phosphorylation was reduced in 5 out of 9 subjects, but, surprisingly, was increased in 4 patients. This indicated that other tyrosine kinases such as Src family kinases might contribute to p27 tyrosine 88 phosphorylation in FLT3-ITD positive AML cells. In fact, incubation with the Src family kinase inhibitor dasatinib could decrease p27 tyrosine 88 phosphorylation in these patient samples, indicating that p27 phosphorylated on tyrosine 88 may be a therapeutic marker for the treatment of AML patients with tyrosine kinase inhibitors.