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Csnk1a1 inhibition ...
Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia
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- Järås, Marcus (author)
- Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine
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Miller, Peter G. (author)
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Chu, Lisa P. (author)
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Puram, Rishi V. (author)
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Fink, Emma C. (author)
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Schneider, Rebekka K. (author)
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Al-Shahrour, Fatima (author)
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- Peña, Pablo (author)
- Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine
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Breyfogle, L. Jordan (author)
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Hartwell, Kimberly A. (author)
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McConkey, Marie E. (author)
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Cowley, Glenn S. (author)
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Root, David E. (author)
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Kharas, Michael G. (author)
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Mullally, Ann (author)
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Ebert, Benjamin L. (author)
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(creator_code:org_t)
- 2014-03-10
- 2014
- English.
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 211:4, s. 605-612
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Järås, Marcus
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Miller, Peter G.
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Chu, Lisa P.
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Puram, Rishi V.
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Fink, Emma C.
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Schneider, Rebek ...
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show more...
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Al-Shahrour, Fat ...
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Peña, Pablo
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Breyfogle, L. Jo ...
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Hartwell, Kimber ...
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McConkey, Marie ...
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Cowley, Glenn S.
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Root, David E.
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Kharas, Michael ...
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Mullally, Ann
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Ebert, Benjamin ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Journal of Exper ...
- By the university
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Lund University