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

Abstract

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.Up to 30% of patients with acute myeloid leukemia 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 1 acute myeloid leukemia;however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-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. (Blood. 2016; 127(23):2890-2902

p27 in FLT3-driven acute myeloid leukemia: many roads lead to ruin

“…17 A recent study found that FLT3-TKI and the CDK4/6 inhibitor palbociclib act synergistically in FLT3-ITD mutant cells. 18 The rationale for this combination is that CDK6 inhibition has effects that go beyond cell cycle control, which would be induced by the TKI-mediated stabilization of p27 without palbociclib. The synergistic effects are mediated by an inhibition of cell-cycle progression in combination with the loss of CDK6-mediated transcription of FLT3, PIM1 and other potential targets.…”

“…The synergistic effects are mediated by an inhibition of cell-cycle progression in combination with the loss of CDK6-mediated transcription of FLT3, PIM1 and other potential targets. 18 As PIM kinases phosphorylate and stabilize FLT3 in vitro, 19 the combined treatment disrupts a vicious cycle and feed-forward loop.…”

Cdk6 contributes to cytoskeletal stability in erythroid cells

“…14–16,43 We now report that Cdk6 promotes the transcription of genes involved in cytoskeletal organization. The function depends on Cdk6 kinase activity: upon loss of Cdk6 kinase activity in erythroid progenitors (R4) there is a significant decrease in mRNA levels of Tubulin alpha-8 implicated in microtubule assembly and Baiap2 , Gelsolin and Pip5k1b involved in actin dynamics.…”

Mechanisms of Resistance to FLT3 Inhibitors and the Role of the Bone Marrow Microenvironment

“…Targeting this mechanism with either the dual CDK4/FLT3-ITD inhibitor, AMG925 46,47 or by adding Palbociclib 48 , a CDK6 inhibitor showed promise to sensitize resistant cells to FLT3 inhibitors.…”