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

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Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. / Järås, Marcus; Miller, Peter G.; Chu, Lisa P.; Puram, Rishi V.; Fink, Emma C.; Schneider, Rebekka K.; Al-Shahrour, Fatima; Peña, Pablo; Breyfogle, L. Jordan; Hartwell, Kimberly A.; McConkey, Marie E.; Cowley, Glenn S.; Root, David E.; Kharas, Michael G.; Mullally, Ann; Ebert, Benjamin L.

I: Journal of Experimental Medicine, Vol. 211, Nr. 4, 2014, s. 605-612.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Järås, M, Miller, PG, Chu, LP, Puram, RV, Fink, EC, Schneider, RK, Al-Shahrour, F, Peña, P, Breyfogle, LJ, Hartwell, KA, McConkey, ME, Cowley, GS, Root, DE, Kharas, MG, Mullally, A & Ebert, BL 2014, 'Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia', Journal of Experimental Medicine, vol. 211, nr. 4, s. 605-612. https://doi.org/10.1084/jem.20131033

APA

Järås, M., Miller, P. G., Chu, L. P., Puram, R. V., Fink, E. C., Schneider, R. K., ... Ebert, B. L. (2014). Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. Journal of Experimental Medicine, 211(4), 605-612. https://doi.org/10.1084/jem.20131033

CBE

Järås M, Miller PG, Chu LP, Puram RV, Fink EC, Schneider RK, Al-Shahrour F, Peña P, Breyfogle LJ, Hartwell KA, McConkey ME, Cowley GS, Root DE, Kharas MG, Mullally A, Ebert BL. 2014. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. Journal of Experimental Medicine. 211(4):605-612. https://doi.org/10.1084/jem.20131033

MLA

Vancouver

Author

Järås, Marcus ; Miller, Peter G. ; Chu, Lisa P. ; Puram, Rishi V. ; Fink, Emma C. ; Schneider, Rebekka K. ; Al-Shahrour, Fatima ; Peña, Pablo ; Breyfogle, L. Jordan ; Hartwell, Kimberly A. ; McConkey, Marie E. ; Cowley, Glenn S. ; Root, David E. ; Kharas, Michael G. ; Mullally, Ann ; Ebert, Benjamin L. / Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. I: Journal of Experimental Medicine. 2014 ; Vol. 211, Nr. 4. s. 605-612.

RIS

TY - JOUR

T1 - Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

AU - Järås, Marcus

AU - Miller, Peter G.

AU - Chu, Lisa P.

AU - Puram, Rishi V.

AU - Fink, Emma C.

AU - Schneider, Rebekka K.

AU - Al-Shahrour, Fatima

AU - Peña, Pablo

AU - Breyfogle, L. Jordan

AU - Hartwell, Kimberly A.

AU - McConkey, Marie E.

AU - Cowley, Glenn S.

AU - Root, David E.

AU - Kharas, Michael G.

AU - Mullally, Ann

AU - Ebert, Benjamin L.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1084/jem.20131033

DO - 10.1084/jem.20131033

M3 - Article

VL - 211

SP - 605

EP - 612

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 1540-9538

IS - 4

ER -