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

Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2012; 122(8):2955-66. DOI: 10.1172/JCI43354
Source: PubMed


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.

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    • "However, only 39% of FLT3-ITD AML patients displayed ERK activation, thus suggesting that seemingly there are other mechanisms responsible for Ser 21 phosphorylation of CEBPA. Thus, it was recently reported that cyclin-dependent kinase 1 (CDK1) is an FLT3-ITD-activated kinase, which is responsible for CEBPA phosphorylation on serine 21 and the blocking of its function [68]. Importantly, inhibition of CDK1 activity relieves the differentiation block in cell lines with mutated FLT3, as well as in primary patient-derived leukemic blast samples [68]. "
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