Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
MEIS1 and CDK1 are downregulated by vitC.
“including MEIS1(ref. 32) and CDK1,33 both of which are downregulated by vitC.”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 53 · Cited by 67
Research works printed but not linked: 1
- Ross SE, et al. Phosphorylation of C/EBPalpha inhib- its granulopoiesis. Mol Cell Biol. 2004;24(2):675-686.
- Authors
- Radomska, H. S., Alberich-Jordà, M., Will, B., Gonzalez, D., Delwel, R., & Tenen, D. G.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Corresponding author
- Tenen, Daniel G.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-08-01
- Volume
- 122
- Issue
- 8
- Pages
- 2955-2966
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3408728
- OpenAlex
- W2081003976
- Cited by
- 67
- References
- 53
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 4 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 9
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- National University of Singapore (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (CA66996)
- National Cancer Institute (R01CA118316, P01 CA 66996, P01CA066996)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK080665)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- CDK1, FLT3-ITD, acute myeloid leukemia, C/EBPα, myeloid differentiation, CDK1 phosphorylation, CDK1 inhibitors, FLT3 inhibitor resistance, granulopoiesis
- MeSH terms
- Animals, Base Sequence, Cell Differentiation, Granulocytes, Humans, Models, Biological, Mutation, Neoplasm Proteins, Phosphorylation, Serine, Transfection, Signal Transduction, Leukemia, Myeloid, Acute, CDC2 Protein Kinase, CCAAT-Enhancer-Binding Protein-alpha, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, fms-Like Tyrosine Kinase 3, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
