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.
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.
- Copyright © 2016 American Society of Hematology