Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML.

Cell
Authors
Keywords
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.

Year of Publication
2016
Journal
Cell
Volume
165
Issue
2
Pages
303-16
Date Published
2016 Apr 07
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2016.03.015
PubMed ID
27058663
PubMed Central ID
PMC4826477
Links
Grant list
R01 HL082945 / HL / NHLBI NIH HHS / United States
T32 HL007901 / HL / NHLBI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
K12 CA087723 / CA / NCI NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States