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 10

Effect of constitutive activation of the FLT3 receptor in leukemogenesis.

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Effect of constitutive activation of the FLT3 receptor in leukemogenesis...
Activation of FLT3 receptor by ITD mutations (stars) promotes cell survival and inhibits apoptosis by activation of STAT3, STAT5, and AKT. Differentiation of myeloid precursors is mediated by the C/EBPα transcription factor, which exhibits full maturation-promoting activity when hypophosphorylated on serine 21. Activation of ERK1/2 and/or CDK1 (via increased expression of cyclin B [Cycl B]) leads to hyperphosphorylation of C/EBPα, which abolishes its function and results in a differentiation block. Broken arrows indicate a likely cascade of downstream pathways from the activated FLT3 leading to upregulation of c-myc and cyclin B. Pharmacological inhibition of either the FLT3, MEK1,or CDK1 pathway results in decreased phosphorylation of C/EBPα on serine 21, increase in its activity, and induction of granulopoiesis.