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

Cancer Cell. 2014 Oct 13;26(4):509-20. doi: 10.1016/j.ccr.2014.08.001. Epub 2014 Sep 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Base Sequence
  • Casein Kinase I / genetics
  • Casein Kinase I / metabolism*
  • Chromosome Deletion*
  • Chromosomes, Human, Pair 5*
  • DNA Primers
  • Female
  • Flow Cytometry
  • Haploinsufficiency
  • Humans
  • Male
  • Mice
  • Mutation
  • Myelodysplastic Syndromes / genetics*
  • Polymerase Chain Reaction
  • Young Adult

Substances

  • DNA Primers
  • Casein Kinase I