Article

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: 13.77). 07/2012; 122(8):2955-66. DOI: 10.1172/JCI43354
Source: PubMed

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.

Download full-text

Full-text

Available from: Hanna Radomska, Jul 05, 2015
0 Followers
 · 
121 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The interaction between the receptor Flt3 and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells. Mutation or over-expression of the flt3 gene, leading to constitutive signalling, enhance the survival and expansion of a variety of leukaemias and is associated with an unfavourable clinical outcome for acute myeloid leukaemia (AML) patients. In this study, we used a murine cellular model for AML and primary leukaemic cells from AML patients to investigate the molecular mechanisms underlying the regulation of flt3 gene expression and identify its key cis- and trans-regulators. By assessing DNA accessibility and epigenetic markings, we defined regulatory domains in the flt3 promoter and first intron. These elements permit in vivo binding of several AML-related transcription factors, including the proto-oncogene MYB and the CCAAT/enhancer binding protein C/EBPα, which are recruited to the flt3 promoter and intronic module, respectively. Substantiating their relevance to the human disease, our analysis of gene expression profiling arrays from AML patients uncovered significant correlations between FLT3 expression level and that of MYB and CEBPA. The latter relationship permits discrimination between patients with CEBPA mono- and bi-allelic mutations, and thus connects two major prognostic factors for AML.Leukemia accepted article preview online, 23 January 2013; doi:10.1038/leu.2013.23.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2013; DOI:10.1038/leu.2013.23 · 9.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several mitotic kinases and kinesins are currently considered as cancer targets based on their critical role during the cell division cycle and their significant level of expression in human tumors. Yet, their use is limited by the lack of selectivity against tumor cells, the low percentage of mitotic cells in many human tumors, and dose-limiting side-effects. As a consequence, initial clinical trials have shown limited responses. Despite these drawbacks, inhibiting mitosis is a promising strategy that deserves further development. Future advances will benefit from more specific inhibitors with better pharmacodynamic properties, a clear physiological characterization and cell-type-specific requirements of old and new mitotic targets, and rational strategies based on synthetic lethal interactions to improve selectivity against tumor cells.
    Current Opinion in Pharmacology 04/2013; 13(4). DOI:10.1016/j.coph.2013.03.011 · 4.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alterations in cell cycle pathways and retinoic acid signaling are implicated in leukemogenesis. However, little is known about the roles of cyclin-dependent kinases (CDKs) in treatment response of leukemia. In this study, we observed that CDK1 expression was significantly higher in bone marrow from 42 patients with acute myeloid leukemia (AML) at recurrence than that at first diagnosis (p = 0.04). AML patients had higher level of nuclear CDK1 in their leukemic blasts tended to have poorer clinical outcome compared with those with lower levels. We showed that CDK1 function is required for all-trans retinoic acid (ATRA) to achieve the optimal effect in U-937 human leukemic cells. CDK1 modulates the levels of P27 (kip) and AKT phosphorylation in response to ATRA treatment. Further, we show, for the first time, that RARγ in concert with ATRA regulates protein levels of CDK1 and its subcellular localization. The regulation of the subcellular content of CDK1 and RARγ by ATRA is an important process for achieving an effective response in treatment of leukemia. RARγ and CDK1 form a reciprocal regulatory circuit in the nucleus and influence the function and protein stability of each other and the level of P27 (kip) protein. In addition, expression of wee1 kinase and Cdc25A/C phosphatases also coincide with CDK1 expression and its subcellular localization in response to ATRA treatment. Our study reveals a novel mechanism by which CDK1 and RARγ coordinate with ATRA to influence cell cycle progression and cellular differentiation.
    Cell cycle (Georgetown, Tex.) 04/2013; 12(8). DOI:10.4161/cc.24313 · 5.01 Impact Factor