title: Histone methyltransferase Suv39h1 deficiency prevents Myc-induced chromosomal instability in murine myeloid leukemias.
abstract: Suv39h1 mediates heterochromatin formation in pericentric and telomeric regions by trimethylation of lysine 9 of histone 3 (H3K9me3). Yet, its role in the induction of chromosomal instability is poorly understood. We established a leukemia model by retrovirally expressing Myc in wild-type and histone methyltransferase Suv39h1-deficient hematopoietic cells and characterized the resulting leukemias for chromosomal instability. All mice that received cells overexpressing Myc developed myeloid leukemia with a median survival of 44 days posttransplantation. Myc-overexpressing wild-type leukemias demonstrated clones with numerical chromosomal aberrations (5/16). In secondary transplantations of these leukemic cells, structural changes, mostly end-to-end fusions of chromosomes, appeared (10/12). In contrast, leukemic cells overexpressing Myc with reduced or no Suv39h1 expression had a normal karyotype in primary, secondary, and tertiary transplantations (16/16). Myc-transduced Suv39h1-deficient cells showed less critically short telomeres (P < 0.05) compared with Myc-transduced wild-type bone marrow cells. Gene expression analysis showed upregulation of genes involved in the alternative lengthening of telomeres (ALT) mechanism. Thus, we hypothesize that loss of Suv39h1 implies activation of the ALT mechanism, in turn ensuring telomere length and stability. Our data show for the first time that Suv39h1 deficiency may prevent chromosomal instability by more efficient telomere stabilization in hematopoietic bone marrow cells overexpressing Myc.
authors: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors: Beate
authors: B
authors: Vajen
authors: Ute
authors: U
authors: Modlich
authors: Andrea
authors: A
authors: Schienke
authors: Susanne
authors: S
authors: Wolf
authors: Britta
authors: B
authors: Skawran
authors: Winfried
authors: W
authors: Hofmann
authors: Guntram
authors: G
authors: Büsche
authors: Hans
authors: H
authors: Kreipe
authors: Christopher
authors: C
authors: Baum
authors: Irene
authors: I
authors: Santos-Barriopedro
authors: Alejandro
authors: A
authors: Vaquero
authors: Brigitte
authors: B
authors: Schlegelberger
authors: Cornelia
authors: C
authors: Rudolph
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D043171:Chromosomal Instability; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032681:Spectral Karyotyping; D016615:Telomere / Q000235:genetics; D059505:Telomere Homeostasis / Q000235:genetics; D059506:Telomere Shortening / Q000235:genetics
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases