Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

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title = "Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML",
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 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.",
author = "Puram, {Rishi V} and Kowalczyk, {Monika S} and {de Boer}, {Carl G} and Schneider, {Rebekka K} and Miller, {Peter G} and Marie McConkey and Zuzana Tothova and H{\'e}ctor Tejero and Dirk Heckl and Marcus J{\"a}r{\aa}s and Chen, {Michelle C} and Hubo Li and Alfred Tamayo and Cowley, {Glenn S} and Orit Rozenblatt-Rosen and Fatima Al-Shahrour and Aviv Regev and Ebert, {Benjamin L}",
note = "Copyright {\circledC} 2016 Elsevier Inc. All rights reserved.",
year = "2016",
doi = "10.1016/j.cell.2016.03.015",
language = "English",
volume = "165",
pages = "303--16",
journal = "Cell.",
issn = "1097-4172",
publisher = "Cell Press",
number = "2",