Methylome Profiling Reveals Distinct Alterations in Phenotypic and Mutational Subgroups of Myeloproliferative Neoplasms

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-02, Vol.73 (3), p.1076-1085
• Main Authors: NISCHAL, Sangeeta, BHATTACHARYYA, Sanchari, PARDANANI, Animesh, MCDEVITT, Michael, MACIEJEWSKI, Jaroslaw P, MELNICK, Ari M, GREALLY, John M, STEIDL, Ulrich, MOLITERNO, Alison, VERMA, Amit, CHRISTOPEIT, Maximilian, YITING YU, LI ZHOU, BHAGAT, Tushar D, SOHAL, Davendra, WILL, Britta, YONGKAI MO, SUZUKI, Masako
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Cell Line, Tumor; Decitabine; Dioxygenases; DNA Methylation; DNA-Binding Proteins - genetics; Female; Hematologic and hematopoietic diseases; Humans; Janus Kinase 2 - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Mutation; Pharmacology. Drug treatments; Polycythemia Vera - genetics; Primary Myelofibrosis - genetics; Proto-Oncogene Proteins - genetics; Repressor Proteins - genetics; Thrombocythemia, Essential - genetics; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-12-0735

Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis than essential thrombocytosis or polycythemia vera, the molecular distinctions between these subgroups are not well elucidated. We conducted the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in polycythemia vera, essential thrombocytosis, and PMF samples compared with healthy controls. We determined that polycythemia vera and essential thrombocytosis are characterized by aberrant promoter hypermethylation, whereas PMF is an epigenetically distinct subgroup characterized by both aberrant hyper- and hypomethylation. Aberrant hypomethylation in PMF was seen to occur in non-CpG island loci, showing further qualitative differences between the disease subgroups. The differentially methylated genes in polycythemia vera and essential thrombocytosis were involved predominantly in cell signaling pathways and were enriched for binding sites of GATA1 and other transcription factors. In contrast, aberrantly methylated genes in PMF were involved in inflammatory pathways and were enriched for NF1, LEF1, and other transcription factors. Within the PMF subgroup, cases with ASXL1 disruptions formed an epigenetically distinct subgroup with relatively increased methylation. Cases of myeloproliferative neoplasms (MPN) with TET2 mutations showed decreased levels of hydroxymethylation and distinct set of hypermethylated genes. In contrast, the JAK2V617F mutation did not drive epigenetic clustering within MPNs. Finally, the significance of aberrant methylation was shown by sensitivity of MPN-derived cell lines to decitabine. These results show epigenetic differences between PMF and polycythemia vera/essential thrombocytosis and reveal methylomic signatures of ASXL1 and TET2 mutations.