Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia
Open accessAbstract
D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.
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All these genes and pathways were previously shown to have significance in pathogenesis of Pre-T ALL.
“All these genes and pathways were previously shown to have significance in the pathogenesis of Pre-T ALL52–54.”
From ASGARD is a single-cell guided pipeline to aid repurposing of drugs (2023) · cites this paper as [52]
In T-cell acute lymphoblastic leukemia, inhibition of CDK6 or genetic repression of cyclin D3 induces apoptosis.
“In T-cell acute lymphoblastic leukemia (T-ALL), inhibition of CDK6 or genetic repression of cyclin D3 induces apoptosis (Choi et al., 2012; Sawai et al., 2012).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Sawai et al., 2012
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- Authors
- Sawai, C. M., Freund, J., Oh, P., Ndiaye-Lobry, D., Bretz, J. C., Strikoudis, A., Genesca, L., Trimarchi, T., Kelliher, M. A., Clark, M., Soulier, J., Chen-Kiang, S., & Aifantis, I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Cornell University (US)
- University of Massachusetts Chan Medical School (US)
- University of Chicago (US)
- Inserm (FR)
- Corresponding author
- Aifantis, Iannis
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 22
- Issue
- 4
- Pages
- 452-465
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3493168
- OpenAlex
- W2087374769
- Cited by
- 183
- References
- 48
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 2 · 2023: 12 · 2022: 18 · 2021: 18 · 2020: 15 · 2019: 17 · 2018: 19 · 2017: 16 · 2016: 12 · 2015: 15 · 2014: 17 · 2013: 10 · 2012: 1
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Leukemia and Lymphoma Society
- New York University
- New York State Stem Cell Science (C026880)
- National Institutes of Health (R21CA141399, RO1CA105129, RO1CA133379, RO1CA149655, RO1GM088847)
- V Foundation for Cancer Research
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- cyclin D3, CDK4/6, T-cell acute lymphoblastic leukemia, cyclin D2, p27, retinoblastoma protein, T cell development, lymphocyte development, cell cycle progression, small-molecule kinase inhibitors, therapeutic target
- MeSH terms
- Animals, Humans, Lymphocytes, Retinoblastoma Protein, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice, Receptor, Notch1, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Cyclin D2, Cyclin D3
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