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Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS

Schneider, Rebekka K.; Ademà, Vera; Heckl, Dirk; Järås, Marcus LU ; Mallo, Mar; Lord, Allegra M.; Chu, Lisa P.; McConkey, Marie E.; Kramann, Rafael and Mullally, Ann, et al. (2014) In Cancer Cell 26(4). p.509-520
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... (More)

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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publication status
published
subject
in
Cancer Cell
volume
26
issue
4
pages
12 pages
publisher
Cell Press
external identifiers
  • scopus:84908006668
ISSN
1535-6108
DOI
10.1016/j.ccr.2014.08.001
language
English
LU publication?
no
id
0381fe62-8f42-401d-ba42-bb573d5de10c
date added to LUP
2017-09-05 11:41:00
date last changed
2017-11-19 04:42:55
@article{0381fe62-8f42-401d-ba42-bb573d5de10c,
  abstract     = {<p>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.</p>},
  author       = {Schneider, Rebekka K. and Ademà, Vera and Heckl, Dirk and Järås, Marcus and Mallo, Mar and Lord, Allegra M. and Chu, Lisa P. and McConkey, Marie E. and Kramann, Rafael and Mullally, Ann and Bejar, Rafael and Solé, Francesc and Ebert, Benjamin L.},
  issn         = {1535-6108},
  language     = {eng},
  month        = {10},
  number       = {4},
  pages        = {509--520},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS},
  url          = {http://dx.doi.org/10.1016/j.ccr.2014.08.001},
  volume       = {26},
  year         = {2014},
}