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

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 6

Induction of granulocytic differentiation following genetic downregulation of CDK1 expression.

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Induction of granulocytic differentiation following genetic downregulati...
(A) shRNA-mediated decreased expression of CDK1 in MOLM-14. MOLM-14 cells were virally transduced with CDK1-targetting shRNA (CDK1 sh) or negative control. Two days later, populations expressing low (Lo), medium (Med), or high (Hi) GFP levels were sorted. Following an additional 2 days of culture, an aliquot of each cell population was lysed and analyzed by Western blot with anti-CDK1 antibody (top panel). β-actin antibody was used for loading control. All samples were loaded on the same gel but were noncontiguous. Quantifications of the band intensities are shown below. Neg, negative for GFP. (B) Downregulation of CDK1 expression leads to granulocytic maturation. Following sorting, cells were cultured for up to 8 more days and their morphology was monitored daily on Wright-Giemsa–stained slides. Original magnification, ×40.