Inactivation of polycomb repressive complex 2 components in myeloproliferative and myelodysplastic/myeloproliferative neoplasms

The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other two core PRC2 components SUZ12 and EED may also bemutational targets in these diseases, as well as associated factors such as Jarid2. SUZ12 mutations were identified in 1 of 2 cases with myelodysplastic/myeloproliferative neoplasm (MDS/MPN) with 17q aUPD and 2 of 2 myelofibrosis cases with focal 17q11 deletions. All three were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 MDS/MPN cases revealed an additional VEFS domain mutant, yielding a total mutation frequency of 2/148 (1.4%). We did not find mutations of Jarid2 or EED in association with aUPD for chromosome 6p or 11q, respectively, however screening unselected cases identified missense mutations in EED (1/148; 1%) and Jarid2 (3/148; 2%). All three SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, thus demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes