Journal Article

DKFZ-2017-05779

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6.

Uras, I. Z. ; Walter, G. (First author)DKFZ* ; Scheicher, R. ; Bellutti, F. ; Prchal-Murphy, M. ; Tigan, A. S. ; Valent, P. ; Heidel, F. H. ; Kubicek, S. ; Scholl, C.DKFZ* ; Fröhling, S.DKFZ* ; Sexl, V.

2016
HighWire Press Stanford, Calif.

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Please use a persistent id in citations: doi:10.1182/blood-2015-11-683581

Abstract: 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.

Keyword(s): Mutant Proteins ; Piperazines ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Pyridines ; FLT3 protein, human ; fms-Like Tyrosine Kinase 3 ; PIM3 protein, human ; Protein-Serine-Threonine Kinases ; CDK6 protein, human ; Cyclin-Dependent Kinase 6 ; palbociclib

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Contributing Institute(s):

1. Translationale Onkologie (G100)
2. Angewandte Funktionelle Genomik (G102)
3. DKTK Heidelberg (L101)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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