Polycomb repressive complex 2 (PRC2) suppresses Eμ-myc lymphoma

• Published in: Blood 2013-10, Vol.122 (15), p.2654-2663
• Main Authors: Lee, Stanley C.W., Phipson, Belinda, Hyland, Craig D., Leong, Huei San, Allan, Rhys S., Lun, Aaron, Hilton, Douglas J., Nutt, Stephen L., Blewitt, Marnie E., Smyth, Gordon K., Alexander, Warren S., Majewski, Ian J.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - physiology; Cells, Cultured; Enhancer of Zeste Homolog 2 Protein; Gene Expression Regulation, Neoplastic - physiology; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Lymphoma, B-Cell - pathology; Lymphopoiesis - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Polycomb Repressive Complex 1 - genetics; Polycomb Repressive Complex 1 - metabolism; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-02-484055

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. •PRC1 and PRC2 have opposing activity in Eμ-myc lymphoma.•Inhibition of PRC2 leads to increased self-renewal in B-cell progenitors.