title: Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin.
abstract: Inhibitor of DNA binding 1 (Id1) functions as an E protein inhibitor, and overexpression of Id1 is seen in acute myeloid leukemia (AML) patients. To define the effects of Id1 on leukemogenesis, we expressed MLL-AF9 in fetal liver (FL) cells or bone marrow (BM) cells isolated from wild-type, Id1(-/-), p21(-/-), or Id1(-/-)p21(-/-) mice, and transplanted them into syngeneic recipient mice. We found that although mice receiving MLL-AF9-transduced FL or BM cells develop AML, loss of Id1 significantly prolonged the median survival of mice receiving FL cells but accelerated leukemogenesis in recipients of BM cells. Deletion of Cdkn1a (p21), an Id1 target gene, can rescue the effect of Id1 loss in both models, suggesting that Cdkn1a is a critical target of Id1 in leukemogenesis. It has been suggested that the FL transplant model mimics human fetal-origin (infant) MLL fusion protein (FP)-driven leukemia, whereas the BM transplantation model resembles postnatal MLL leukemia; in fact, the analysis of clinical samples from patients with MLL-FP(+) leukemia showed that Id1 expression is elevated in the former and reduced in the latter type of MLL-FP(+) AML. Our findings suggest that Id1 could be a potential therapeutic target for infant MLL-AF9-driven leukemia.
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Na
authors.initials: N
authors.lastname: Man
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Sun
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Yurong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Marta
authors.initials: M
authors.lastname: García-Cao
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Guoyan
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Megan
authors.initials: M
authors.lastname: Hatlen
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Ronit
authors.initials: R
authors.lastname: Shah
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Nolan
authors.initials: N
authors.lastname: Chastain
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/School of Medicine, Shanghai Jiao Tong University, Shanghai, China;
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Tianjin, China;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Tianjin, China;
authors.forename: Mengyao
authors.initials: M
authors.lastname: Sheng
authors.affiliation: Pediatric Hematology and Oncology, Shanghai Children's Medical Center, Shanghai, China; and.
authors.forename: Junhong
authors.initials: J
authors.lastname: Song
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL;
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY;
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL; State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/School of Medicine, Shanghai Jiao Tong University, Shanghai, China;
authors.forename: Lan
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion