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Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

Iris Z. Uras, Gina J. Walter, Ruth Scheicher, Florian Bellutti, Michaela Prchal-Murphy, Anca S. Tigan, Peter Valent, Florian H. Heidel, Stefan Kubicek, Claudia Scholl, Stefan Fröhling and Veronika Sexl

Key points

  • CDK6 directly regulates transcription of FLT3 and PIM1 in a kinase-dependent manner.

  • CDK6 kinase inhibition impairs not only FLT3-dependent cell growth in vitro but also FLT3-driven leukemogenesis in vivo.

Abstract

Up to 30% of patients with acute myeloid leukemia (AML) have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD+ AML; however, their use is complicated by rapid development of resistance, illustrating the need for additional therapeutic targets. We show that the FDA-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors.

  • Submitted November 23, 2015.
  • Accepted April 11, 2016.