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Role of Casein Kinase 1A1 in the Biology and Targeted Therapy of del(5q) MDS
Open accessAbstract
The casein kinase 1A1 gene (CSNK1A1) is a putative tumor suppressor gene located in the common deleted region for del(5q) myelodysplastic syndrome (MDS). We generated a murine model with conditional inactivation of Csnk1a1 and found that Csnk1a1 haploinsufficiency induces hematopoietic stem cell expansion and a competitive repopulation advantage, whereas homozygous deletion induces hematopoietic stem cell failure. Based on this finding, we found that heterozygous inactivation of Csnk1a1 sensitizes cells to a CSNK1 inhibitor relative to cells with two intact alleles. In addition, we identified recurrent somatic mutations in CSNK1A1 on the nondeleted allele of patients with del(5q) MDS. These studies demonstrate that CSNK1A1 plays a central role in the biology of del(5q) MDS and is a promising therapeutic target.
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“CK1α is essential for the survival of hematopoietic stem cells, and heterozygous deletion of its gene in del(5q) myelodysplastic syndrome provides a therapeutic window for eliminating the malignant stem cell clone (10).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [10]
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“However, lenalidomide-induced degradation of the remaining cK1α mimics biallelic loss of CSNK1A1 which triggers p53 activation, enhances apoptosis and leads to clonal arrest of the 5q-deleted population which ultimately drives disease regression (wei et al. 2009;Schneider et al. 2014;Krönke et al. 2015).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Schneider et al. 2014
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“Accordingly, mutations in TP53 lead to resistance to lenalidomide in patients with MDS97,98 (FIG. 3).”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [98]
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“Consistent with these experimental findings, resistance to lenalidomide and disease progression are associated with an increased frequency of TP53 mutations in patients with del(5q) MDS98,161,162.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [98]
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“CK1a is essential for the survival of hematopoietic stem cells, and heterozygous deletion of its gene in del(5q) myelodysplastic syndrome provides a therapeutic window for eliminating the malignant stem cell clone (10).”
BackgroundSelf-citation
Metadata
- Authors
- Schneider, R. K., Ademà, V., Heckl, D., Järås, M., Mallo, M., Lord, A. M., Chu, L. P., McConkey, M. E., Kramann, R., Mullally, A., Bejar, R., Solé, F., & Ebert, B. L.
- Affiliations
- Brigham and Women's Hospital (US)
- Universitat Autònoma de Barcelona (ES)
- University of California San Diego (US)
- Broad Institute (US)
- Corresponding author
- Ebert, Benjamin L.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 26
- Issue
- 4
- Pages
- 509-520
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4199102
- OpenAlex
- W2081870738
- Cited by
- 188
- References
- 52
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 10 · 2023: 5 · 2022: 16 · 2021: 18 · 2020: 16 · 2019: 13 · 2018: 20 · 2017: 24 · 2016: 22 · 2015: 19 · 2014: 1
- FWCI
- 15.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Leukemia and Lymphoma Society
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Harvard Stem Cell Institute
- National Heart, Lung, and Blood Institute (R01HL082945)
- National Cancer Institute (P30CA023100, P01CA066996)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK091360)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- CSNK1A1, del(5q) myelodysplastic syndrome, tumor suppressor, haploinsufficiency, hematopoietic stem cells, competitive repopulation, conditional knockout mouse model, somatic mutations, therapeutic target
- MeSH terms
- Aged, Animals, Base Sequence, Chromosome Deletion, Chromosomes, Human, Pair 5, Female, Flow Cytometry, Humans, Male, Mutation, Myelodysplastic Syndromes, Polymerase Chain Reaction, DNA Primers, Casein Kinase I, Mice, Young Adult, Haploinsufficiency
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