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Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Järås, Marcus LU ; Miller, Peter G.; Chu, Lisa P.; Puram, Rishi V.; Fink, Emma C.; Schneider, Rebekka K.; Al-Shahrour, Fatima; Peña, Pablo LU ; Breyfogle, L. Jordan and Hartwell, Kimberly A., et al. (2014) In Journal of Experimental Medicine 211(4). p.605-612
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 alpha (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... (More)
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 alpha (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. (Less)
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publication status
published
subject
in
Journal of Experimental Medicine
volume
211
issue
4
pages
605 - 612
publisher
Rockefeller University Press
external identifiers
  • wos:000334917400003
  • scopus:84897943177
ISSN
1540-9538
DOI
10.1084/jem.20131033
language
English
LU publication?
yes
id
f0ff78b7-c677-4314-bde5-8da1a7b0925c (old id 4488752)
date added to LUP
2014-07-01 07:34:35
date last changed
2017-11-19 03:48:24
@article{f0ff78b7-c677-4314-bde5-8da1a7b0925c,
  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 alpha (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.},
  author       = {Järås, Marcus and Miller, Peter G. and Chu, Lisa P. and Puram, Rishi V. and Fink, Emma C. and Schneider, Rebekka K. and Al-Shahrour, Fatima and Peña, Pablo and Breyfogle, L. Jordan and Hartwell, Kimberly A. and McConkey, Marie E. and Cowley, Glenn S. and Root, David E. and Kharas, Michael G. and Mullally, Ann and Ebert, Benjamin L.},
  issn         = {1540-9538},
  language     = {eng},
  number       = {4},
  pages        = {605--612},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia},
  url          = {http://dx.doi.org/10.1084/jem.20131033},
  volume       = {211},
  year         = {2014},
}