Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.
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.
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Iris Z
IZ
Uras
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany;
Gina J
GJ
Walter
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Ruth
R
Scheicher
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Florian
F
Bellutti
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Michaela
M
Prchal-Murphy
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Anca S
AS
Tigan
Division of Hematology and Hemostaseology, Department of Internal Medicine I, and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria;
Peter
P
Valent
Department of Hematology and Oncology, Center for Internal Medicine II, Jena University Hospital, Jena, Germany;
Florian H
FH
Heidel
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; and.
Stefan
S
Kubicek
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany;
Claudia
C
Scholl
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; German Cancer Consortium, Heidelberg, Germany; Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
Stefan
S
Fröhling
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria;
Veronika
V
Sexl
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism / Q000502:physiology*; D005260:Female; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011725:Pyridines / Q000494:pharmacology*; D020080:Tandem Repeat Sequences; D015533:Transcriptional Activation / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D050505:Mutant Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib