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

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Prchal-Murphy, Michaela; Sexl, Veronika

Abstrakt

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+ 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.

Dokumententyp

Originalarbeit

ISSN/eISSN

0006-4971 - 1528-0020

WoS ID

WOS:000378335900020

Projekt

Die CDK6/p16INK4A Achse - Bedeutung für Hämatopoese und Lymphom-entstehung