Abstract
The circadian rhythm transcription factors CLOCK and BMAL1 are essential for AML cell growth.
Major finding: The circadian rhythm transcription factors CLOCK and BMAL1 are essential for AML cell growth.
Concept: AML cells and HSCs have an intact circadian clock, but AML cells are more sensitive to disruption.
Impact: Targeting the circadian rhythm genes may reduce AML growth and promote differentiation.
Acute myeloid leukemias (AML) often exhibit transcription factor dependencies that may drive leukemogenesis by preventing differentiation and generating leukemia stem cells that are essential for disease initiation and progression. Puram and colleagues performed an in vivo shRNA screen to identify leukemia-specific transcription factor dependencies in a serial transplantation model of AML driven by MLL–AF9, and found 35 transcriptional regulators that are likely essential for AML cells, including two circadian rhythm genes, Clock and Bmal1, which function as a heterodimer in circadian clock regulation. The circadian clock has known functions in the hematopoietic system and has previously been shown to regulate cellular proliferation, and thus may be a potential driver for cancer. Disruption of the circadian rhythm through inhibition of BMAL1 transcription with the small molecule SR9011 resulted in an increase in myeloid differentiation markers and a reduction in actively dividing cells. Further, murine AML cells and normal HSCs exhibited a functional circadian clock, as luciferase fused to the clock gene Per2 resulted in bioluminescence oscillations within a period of approximately 24 hours. In human AML cells CLOCK and BMAL1 heterodimers were enriched at genes involved in the circadian rhythm, suggesting a functional circadian clock. Moreover, human AML cell lines were sensitive to CLOCK and BMAL1 knockdown. Specific hematopoietic deletion of Bmal1 did not result in hematopoietic defects, indicating that Bmal1 loss is well tolerated in adult hematopoiesis and suggesting that clock gene inhibition may selectively target cancer cells. Conditional deletion of Bmal1 in murine MLL–AF9 leukemia resulted in a shortened survival, and AML cells were more sensitive to circadian disruption with SR9011 than normal hematopoietic cells. Together, these results indicate AML cell dependence on the circadian rhythm genes CLOCK and BMAL1, and suggest that the clock genes may be effective therapeutic targets in AML.
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