title: Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia.
abstract: Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.forename: Peter G
authors.initials: PG
authors.lastname: Miller
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Chu
authors.forename: Rishi V
authors.initials: RV
authors.lastname: Puram
authors.forename: Emma C
authors.initials: EC
authors.lastname: Fink
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.forename: Pablo
authors.initials: P
authors.lastname: Peña
authors.forename: L Jordan
authors.initials: LJ
authors.lastname: Breyfogle
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hartwell
authors.forename: Marie E
authors.initials: ME
authors.lastname: McConkey
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000818:Animals; D048128:Casein Kinase Ialpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D038601:Ribosomal Protein S6 / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; C448579:ribosomal protein S6, mouse; D048128:Casein Kinase Ialpha