Acute myeloid leukemia (AML) accounts for 90% of acute leukemias in adult and 15-20% of those in children. AML is a genetically heterogeneous blood cancer associated with a variety of genomic alterations. The discovery of recurrent mutations in protein-coding genes has provided successful targets for diagnosis, prognosis and therapies; however, it remains elusive how alterations within non-coding DNA sequences, consisting of 98.5% of human genome, contribute to AML development. The challenge is twofold: 1) to establish causality of non-coding mutations, and 2) to distinguish oncogenic non-coding drivers from non-functional genetic variants. Enhancers are non-coding DNA sequences that determi...

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Acute myeloid leukemia (AML) accounts for 90% of acute leukemias in adult and 15-20% of those in children. AML is a genetically heterogeneous blood cancer associated with a variety of genomic alterations. The discovery of recurrent mutations in protein-coding genes has provided successful targets for diagnosis, prognosis and therapies; however, it remains elusive how alterations within non-coding DNA sequences, consisting of 98.5% of human genome, contribute to AML development. The challenge is twofold: 1) to establish causality of non-coding mutations, and 2) to distinguish oncogenic non-coding drivers from non-functional genetic variants. Enhancers are non-coding DNA sequences that determine cell identity by controlling gene expression. We recently generated the first enhancer mutational landscape in human leukemia, and identified the circadian clock gene PER2 as the top candidate gene harboring recurrent non-coding mutations at its enhancer in AML. Strikingly, PER2 enhancer mutations locate within the binding sites of nuclear receptor (NR) transcription factors, and significantly attenuated NR-mediated PER2 activation in AML cells. These results establish a new molecular link between non-coding mutations, NR signaling and PER2 expression in cancer. Emerging evidence points to a critical role of circadian genes in tumorigenesis; however, the function and regulation of PER2 in leukemogenesis remained unknown. The goals of this project are to determine the role of PER2 and its enhancer in AML, to characterize the mechanisms of PER2 enhancer mutations in signaling-dependent gene expression, and to identify pathogenic non-coding mutations that modulate NR signaling in leukemia. The accomplishment of this project will not only elucidate the mechanistic role of non-coding mutations in leukemia, but also provide new tools for comprehensive analysis of non-coding cancer variants as new regulators of leukemogenesis.

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