title: Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression.
abstract: Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21)(+) leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/Akt1 signaling as a potential therapeutic target in t(8;21) leukemia.
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, and.
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, and.
authors.forename: Na
authors.initials: N
authors.lastname: Man
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Cell Biology, University of Miami Miller School of Medicine, Miami, FL;
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Sun
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, and.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Tan
authors.forename: Marta
authors.initials: M
authors.lastname: García-Cao
authors.affiliation: Cancer Biology and Genetics Program, Sloan Kettering Institute and.
authors.forename: Marta Garcia
authors.initials: MG
authors.lastname: Cao
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, and.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Megan
authors.initials: M
authors.lastname: Hatlen
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Meredith
authors.initials: M
authors.lastname: Mattlin
authors.affiliation: Institute of Human Genomics and.
authors.forename: Arpit
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Institute of Human Genomics and.
authors.forename: Evadnie
authors.initials: E
authors.lastname: Rampersaud
authors.affiliation: Cancer Biology and Genetics Program, Sloan Kettering Institute and.
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, and Department of Medicine, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051796:Inhibitor of Differentiation Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014178:Translocation, Genetic
chemical_list: C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D047428:Protein Kinase Inhibitors; C067679:Idb3 protein, mouse; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt