Abstract 617

Single nucleotide polymorphism (SNP) arrays have revealed regions of acquired uniparental disomy (aUPD) as recurrent events in hematological malignancies. Some of these regions are associated with the acquisition of somatic mutations in specific genes but the presumptive targets of many stretches of aUPD remain to be identified. We and others recently identified EZH2 as a target for 7q aUPD in myeloid malignancies, specifically myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN). EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. We reasoned that the other two core PRC2 components SUZ12 and EED may also be mutational targets in these diseases, as well as associated factors such as Jarid2. We identified SUZ12 mutations in 1 of 2 cases with 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, necessary for the interaction between SUZ12 and EZH2 and thought to help stabilize the PRC2 complex. 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 additional cases identified missense mutations in EED (1/87; 1%) and Jarid2 (3/148; 2%). All three SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase (HMT) activity as assessed by an in vitro baculovirus expression assay, thus demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes. SUZ12 is located at 17q11.2 close to NF1, a gene that encodes a negative regulator of Ras signalling that has been strongly implicated in the pathogenesis of myeloid neoplasms. Of the cases with SUZ12 mutations, one with del(17q11.2) had mutations of both NF1 and SUZ12. Both of these mutations were clearly inactivating: a frameshift in exon 5 of NF1 and a D605V change in SUZ12 that greatly reduced PRC2 HMT activity. In summary, we have shown that inactivation of the PRC2 can occur through mutation of any of the 3 core components, and that inactivating mutations of EZH2, SUZ12 or EED are seen in 15% of cases of MDS/MPN. These findings emphasize the importance of PRC2 function in hemopoiesis and suggest that deregulation of the epigenetic control of gene expression plays an important role in the development of myeloid disorders.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.