Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia Journal Article
| Authors: | Järås, M.; Miller, P. G.; Chu, L. P.; Puram, R. V.; Fink, E. C.; Schneider, R. K.; Al-Shahrour, F.; Peña, P.; Breyfogle, L. J.; Hartwell, K. A.; McConkey, M. E.; Cowley, G. S.; Root, D. E.; Kharas, M. G.; Mullally, A.; Ebert, B. L. |
| Article 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. © 2014 Järås et al. |
| Keywords: | controlled study; protein expression; protein phosphorylation; unclassified drug; acute granulocytic leukemia; nonhuman; drug targeting; animal cell; mouse; animal tissue; cell survival; enzyme inhibition; gene expression profiling; animal experiment; animal model; in vivo study; cell differentiation; antineoplastic activity; drug effect; enzyme inhibitor; enzyme activity; protein serine threonine kinase; protein p53; leukemia cell; bone marrow cell; hematopoietic stem cell; gene silencing; molecular biology; short hairpin rna; concentration response; protein s6; priority journal; article; casein kinase ialpha; casein kinase ialpha 1; d 4476 |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 211 |
| Issue: | 4 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2014-03-10 |
| Start Page: | 605 |
| End Page: | 612 |
| Language: | English |
| DOI: | 10.1084/jem.20131033 |
| PROVIDER: | scopus |
| PMCID: | PMC3978274 |
| PUBMED: | 24616378 |
| DOI/URL: | |
| Notes: | Export Date: 1 May 2014 -- CODEN: JEMEA -- Source: Scopus |
