title: Ectopic TLX1 expression accelerates malignancies in mice deficient in DNA-PK.
abstract: The noncluster homeobox gene HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHμ-TLX1(Tg) mice which develop mature B cell lymphoma after a long latency period, suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHμ-TLX1(Tg) mice with mice deficient in the DNA repair enzyme DNA-PK (Prkdc(Scid/Scid) mice). IgHµ-TLX1(Tg)Prkdc(Scid/Scid) mice developed T-ALL and acute myeloid leukemia (AML) with reduced latency relative to control Prkdc(Scid/Scid) mice. Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index. Moreover, premalignant and malignant thymocytes exhibited impaired spindle checkpoint function, in association with aneuploid karyotypes. Gene expression profiling of premalignant IgHµ-TLX1(Tg)Prkdc(Scid/Scid) thymocytes revealed dysregulated expression of cell cycle, apoptotic and mitotic spindle checkpoint genes in double negative 2 (DN2) and DN3 stage thymocytes. Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Krutikov
authors.affiliation: Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Yanzhen
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alden
authors.initials: A
authors.lastname: Chesney
authors.affiliation: Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Vaags
authors.affiliation: Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Valentina
authors.initials: V
authors.lastname: Evdokimova
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Hough
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000172:deficiency*; D004268:DNA-Binding Proteins / Q000172:deficiency*; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000172:deficiency*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology; D013953:Thymus Neoplasms / Q000737:chemistry; D059467:Transcriptome
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C487378:Tlx1 protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse