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Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

Puram, Rishi V; Kowalczyk, Monika S; de Boer, Carl G; Schneider, Rebekka K; Miller, Peter G; McConkey, Marie; Tothova, Zuzana; Tejero, Héctor; Heckl, Dirk and Järås, Marcus LU , et al. (2016) In Cell 165(2). p.16-303
Abstract

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that... (More)

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.

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published
subject
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Cell
volume
165
issue
2
pages
14 pages
publisher
Cell Press
external identifiers
  • WOS:000374123000010
  • Scopus:84962852337
ISSN
1097-4172
DOI
10.1016/j.cell.2016.03.015
language
English
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yes
id
acae1bce-1506-4bf6-9fa6-24efa8b6775e
date added to LUP
2016-04-28 14:46:55
date last changed
2016-11-13 04:39:02
@misc{acae1bce-1506-4bf6-9fa6-24efa8b6775e,
  abstract     = {<p>Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes required for the growth of AML cells in vitro and in vivo. Disruption of canonical circadian pathway components produces anti-leukemic effects, including impaired proliferation, enhanced myeloid differentiation, and depletion of LSCs. We find that both normal and malignant hematopoietic cells harbor an intact clock with robust circadian oscillations, and genetic knockout models reveal a leukemia-specific dependence on the pathway. Our findings establish a role for the core circadian clock genes in AML.</p>},
  author       = {Puram, Rishi V and Kowalczyk, Monika S and de Boer, Carl G and Schneider, Rebekka K and Miller, Peter G and McConkey, Marie and Tothova, Zuzana and Tejero, Héctor and Heckl, Dirk and Järås, Marcus and Chen, Michelle C and Li, Hubo and Tamayo, Alfred and Cowley, Glenn S and Rozenblatt-Rosen, Orit and Al-Shahrour, Fatima and Regev, Aviv and Ebert, Benjamin L},
  issn         = {1097-4172},
  language     = {eng},
  number       = {2},
  pages        = {16--303},
  publisher    = {ARRAY(0x84ddf38)},
  series       = {Cell},
  title        = {Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML},
  url          = {http://dx.doi.org/10.1016/j.cell.2016.03.015},
  volume       = {165},
  year         = {2016},
}