Normal and Malignant Hematopoietic Stem Cells Have Circadiandependent Regulation of Gene Expression but Leukemic Stem Cells in AML Require Core Circadian Clock Genes. (A) Circadian rhythm is generated by cyclic expression of BMAL1, which is high at the beginning of a subjective day and low at the beginning of a subjective night. When BMAL1 is expressed it forms a heterodimeric transcription factor with CLOCK to directly promote the expression of CRY, PER, and REV-ERBα. CRY, PER, and REV-ERBα then serve to inhibit the expression of BMAL1 and/ or the heterodimerization of BMAL1 to CLOCK. (B) The cyclic expression of these genes are present in normal as well as leukemic stem cells in vivo and Puram et al. have now found that BMAL1 and CLOCK are 1) upregulated by the MLLAF9 fusion oncoprotein and 2) preferentially required in leukemic stem cells over normal hematopoietic stem cells. Moreover, the malignant cells were preferentially sensitive to the compound SR9011, which is an agonist of REV-ERBα and downregulates BMAL1 expression.