title: Epigenetic regulator Smchd1 functions as a tumor suppressor.
abstract: SMCHD1 is an epigenetic modifier of gene expression that is critical to maintain X chromosome inactivation. Here, we show in mouse that genetic inactivation of Smchd1 accelerates tumorigenesis in male mice. Loss of Smchd1 in transformed mouse embryonic fibroblasts increased tumor growth upon transplantation into immunodeficient nude mice. In addition, loss of Smchd1 in Eμ-Myc transgenic mice that undergo lymphomagenesis reduced disease latency by 50% relative to control animals. In premalignant Eμ-Myc transgenic mice deficient in Smchd1, there was an increase in the number of pre-B cells in the periphery, likely accounting for the accelerated disease in these animals. Global gene expression profiling suggested that Smchd1 normally represses genes activated by MLL chimeric fusion proteins in leukemia, implying that Smchd1 loss may work through the same pathways as overexpressed MLL fusion proteins do in leukemia and lymphoma. Notably, we found that SMCHD1 is underexpressed in many types of human hematopoietic malignancy. Together, our observations collectively highlight a hitherto uncharacterized role for SMCHD1 as a candidate tumor suppressor gene in hematopoietic cancers.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Huei San
authors.initials: HS
authors.lastname: Leong
authors.forename: Kelan
authors.initials: K
authors.lastname: Chen
authors.forename: Yifang
authors.initials: Y
authors.lastname: Hu
authors.forename: Stanley
authors.initials: S
authors.lastname: Lee
authors.forename: Jason
authors.initials: J
authors.lastname: Corbin
authors.forename: Miha
authors.initials: M
authors.lastname: Pakusch
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Majewski
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Marnie E
authors.initials: ME
authors.lastname: Blewitt
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005347:Fibroblasts; D055786:Gene Knockout Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C578241:SMCHD1 protein, human