title: Polycomb repressive complex 2 (PRC2) suppresses Eμ-myc lymphoma.
abstract: Deregulation of polycomb group complexes polycomb repressive complex 1 (PRC1) and 2 (PRC2) is associated with human cancers. Although inactivating mutations in PRC2-encoding genes EZH2, EED, and SUZ12 are present in T-cell acute lymphoblastic leukemia and in myeloid malignancies, gain-of-function mutations in EZH2 are frequently observed in B-cell lymphoma, implying disease-dependent effects of individual mutations. We show that, in contrast to PRC1, PRC2 is a tumor suppressor in Eµ-myc lymphomagenesis, because disease onset was accelerated by heterozygosity for Suz12 or by short hairpin RNA-mediated knockdown of Suz12 or Ezh2. Accelerated lymphomagenesis was associated with increased accumulation of B-lymphoid cells in the absence of effects on apoptosis or cell cycling. However, Suz12-deficient B-lymphoid progenitors exhibit enhanced serial clonogenicity. Thus, PRC2 normally restricts the self-renewal of B-lymphoid progenitors, the disruption of which contributes to lymphomagenesis. This finding provides new insight regarding the functional contribution of mutations in PRC2 in a range of leukemias.
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; and.
authors: Stanley C W
authors: SC
authors: Lee
authors: Belinda
authors: B
authors: Phipson
authors: Craig D
authors: CD
authors: Hyland
authors: Huei San
authors: HS
authors: Leong
authors: Rhys S
authors: RS
authors: Allan
authors: Aaron
authors: A
authors: Lun
authors: Douglas J
authors: DJ
authors: Hilton
authors: Stephen L
authors: SL
authors: Nutt
authors: Marnie E
authors: ME
authors: Blewitt
authors: Gordon K
authors: GK
authors: Smyth
authors: Warren S
authors: WS
authors: Alexander
authors: Ian J
authors: IJ
authors: Majewski
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism
chemical_list: C107275:Eed protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C494163:Suz12 protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1