Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS.
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Abstract | 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. |
Year of Publication | 2014
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Journal | Cancer Cell
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Volume | 26
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Issue | 4
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Pages | 509-20
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Date Published | 2014 Oct 13
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ISSN | 1878-3686
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DOI | 10.1016/j.ccr.2014.08.001
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PubMed ID | 25242043
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PubMed Central ID | PMC4199102
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Grant list | R01 HL082945 / HL / NHLBI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P30 CA023100 / CA / NCI NIH HHS / United States
K08 DK091360 / DK / NIDDK NIH HHS / United States
R01HL082945 / HL / NHLBI NIH HHS / United States
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