Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.

The analysis of rare chromosomal translocations in myeloproliferative disorders has highlighted the importance of aberrant tyrosine kinase signaling in the pathogenesis of these diseases. Here we have investigated samples from 679 patients and controls for the nonreceptor tyrosine kinase JAK2 V617F mutation. Of the 480 myeloproliferative disorder (MPD) samples, the proportion of positive cases per disease subtype was 30 (20%) of 152 for atypical or unclassified MPD, 2 of 134 (2%) for idiopathic hypereosinophilic syndrome, 58 of 72 (81%) for polycythemia vera, 24 of 59 (41%) essential thrombocythemia (ET), and 15 of 35 (43%) for idiopathic myelofibrosis. V617F was not identified in patients with systemic mastocytosis (n ‫؍‬ 28), chronic or acute myeloid leukemia (n ‫؍‬ 35), secondary erythrocytosis (n ‫؍‬ 4), or healthy controls (n ‫؍‬ 160). Homozygosity for V617F was seen in 43% of mutant samples and was closely correlated with chromosome 9p uniparental disomy. Homozygosity was significantly less common in ET compared with other MPD subtypes. In 53 cases analyzed, the median level of PRV1 expression was significantly higher in V617F-positive cases compared with cases without the mutation. We conclude that V617F is widespread in MPDs. IntroductionChronic myeloproliferative diseases (CMPDs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid cell lineages in the bone marrow and increased numbers of mature and immature cells in the peripheral blood. CMPDs include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML), plus rarer subtypes such as chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES), and chronic eosinophilic leukemia (CEL). These diseases overlap with myelodysplastic/myeloproliferative diseases (MDS/MPDs) such as atypical CML (aCML) and chronic myelomonocytic leukemia (CMML), in which proliferation is accompanied by dysplastic features or ineffective hematopoiesis in other lineages. 1 We refer here broadly to all these groups as myeloproliferative disorders (MPDs).Although there are strict diagnostic criteria for MPD subtypes, precise categorization remains a subject of debate 2 and furthermore, it can be difficult to differentiate some cases from reactive disorders. Only CML is characterized by a pathognomonic molecular marker, the BCR-ABL fusion, and the primary abnormalities driving excess proliferation in most other cases have been obscure. However, several lines of evidence have implicated aberrant tyrosine kinase signaling as the root cause of MPDs. Breakpoint cluster region-abelson (BCR-ABL) itself is a constitutively active tyrosine kinase that is believed to be the primary, and probably the only, driving force behind chronic-phase CML. 3 Other gene fusions have been identified in rare cases of aCML, CMML, and HES/CEL that involve the tyrosine kinases PDGFRA, PDGFRB, FGFR1, and JAK2. 4,5 In addition, the KIT receptor is activated by point mutation in the majority...

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.