title: Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) remains a therapeutic challenge despite increasing knowledge about the molecular origins of the disease, as the mechanisms of AML cell escape from chemotherapy remain poorly defined. We hypothesized that AML cells are addicted to molecular pathways in the context of chemotherapy and used complementary approaches to identify these addictions. Using novel molecular and computational approaches, we performed genome-wide short-hairpin RNA screens to identify proteins that mediate AML cell fate after cytarabine exposure; gene expression profiling of AML cells exposed to cytarabine to identify genes with induced expression in this context; and examination of existing gene expression data from primary patient samples. Integration of these independent analyses strongly implicates cell-cycle checkpoint proteins, particularly WEE1, as critical mediators of AML cell survival after cytarabine exposure. Knockdown of WEE1 in a secondary screen confirmed its role in AML cell survival. Pharmacologic inhibition of WEE1 in AML cell lines and primary cells is synergistic with cytarabine. Further experiments demonstrate that inhibition of WEE1 prevents S-phase arrest induced by cytarabine, broadening the functions of WEE1 that may be exploited therapeutically. These data highlight the power of integrating functional and descriptive genomics, and identify WEE1 as a potential therapeutic target in AML.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. chris.porter@ucdenver.edu
authors.forename: C C
authors.initials: CC
authors.lastname: Porter
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Fosmire
authors.forename: C M
authors.initials: CM
authors.lastname: Gearheart
authors.forename: A
authors.initials: A
authors.lastname: van Linden
authors.forename: D
authors.initials: D
authors.lastname: Baturin
authors.forename: V
authors.initials: V
authors.lastname: Zaberezhnyy
authors.forename: P R
authors.initials: PR
authors.lastname: Patel
authors.forename: D
authors.initials: D
authors.lastname: Gao
authors.forename: A C
authors.initials: AC
authors.lastname: Tan
authors.forename: J
authors.initials: J
authors.lastname: DeGregori
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000187:drug effects; D023281:Genomics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D003561:Cytarabine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human