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Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα
Hanna S. Radomska, … , Ruud Delwel, Daniel G. Tenen
Hanna S. Radomska, … , Ruud Delwel, Daniel G. Tenen
Published July 17, 2012
Citation Information: J Clin Invest. 2012;122(8):2955-2966. https://doi.org/10.1172/JCI43354.
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Research Article Oncology

Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα

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Abstract

Mutations that activate the fms-like tyrosine kinase 3 (FLT3) receptor are among the most prevalent mutations in acute myeloid leukemias. The oncogenic role of FLT3 mutants has been attributed to the abnormal activation of several downstream signaling pathways, such as STAT3, STAT5, ERK1/2, and AKT. Here, we discovered that the cyclin-dependent kinase 1 (CDK1) pathway is also affected by internal tandem duplication mutations in FLT3. Moreover, we also identified C/EBPα, a granulopoiesis-promoting transcription factor, as a substrate for CDK1. We further demonstrated that CDK1 phosphorylates C/EBPα on serine 21, which inhibits its differentiation-inducing function. Importantly, we found that inhibition of CDK1 activity relieves the differentiation block in cell lines with mutated FLT3 as well as in primary patient–derived peripheral blood samples. Clinical trials with CDK1 inhibitors are currently under way for various malignancies. Our data strongly suggest that targeting the CDK1 pathway might be applied in the treatment of FLT3ITD mutant leukemias, especially those resistant to FLT3 inhibitor therapies.

Authors

Hanna S. Radomska, Meritxell Alberich-Jordà, Britta Will, David Gonzalez, Ruud Delwel, Daniel G. Tenen

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Figure 3

Inhibition of constitutive activity of FLT3 decreases CDK1 kinase activity in FLT3ITD AML cells and slows down the cell-cycle progression.

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Inhibition of constitutive activity of FLT3 decreases CDK1 kinase activi...
(A) CDK1 was immunoprecipitated from FLT3ITD-expressing cell lines (MV4;11, MOLM-13, and MOLM-14) and used in kinase reactions with histone H1 as a substrate and 32P. Proteins were separated on acrylamide gels and blotted to nitrocellulose membranes. The top panel shows the autoradiograph of the blot, and the bottom panel shows staining with anti-CDK1 antibody to assure that equal amounts of CDK1 were immunoprecipitated. The assay was done either in the absence of treatment (–; lanes 1, 4, and 7), after 24-hour treatment with 0.1% DMSO (DMSO; lanes 2, 5, and 8), or after 24-hour treatment with FLT3 inhibitor (MLN518; lanes 3, 6, and 9). The percentages indicate the CDK1 activities remaining after FLT3 inhibitor treatment (DMSO-treated samples were set to 100%). (B) Cell-cycle distribution of MOLM-14 cells treated with DMSO (left panel) or FLT3 inhibitor MLN518 (right panel). Inhibition of FLT3 arrests majority of MOLM-14 cells at G0. Numbers indicate the percentage of cells in each quadrant.

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