TitleMethylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms.
Publication TypeJournal Article
Year of Publication2013
AuthorsNischal, Sangeeta, Bhattacharyya Sanchari, Christopeit Maximilian, Yu Yiting, Zhou Li, Bhagat Tushar D., Sohal Davendra, Will Britta, Mo Yongkai, Suzuki Masako, Pardanani Animesh, McDevitt Michael, Maciejewski Jaroslaw P., Melnick Ari M., Greally John M., Steidl Ulrich, Moliterno Alison, and Verma Amit
JournalCancer Res
Date Published2013 Feb 01
KeywordsAdult, Aged, Aged, 80 and over, Azacitidine, Cell Line, Tumor, Decitabine, Dioxygenases, DNA Methylation, DNA-Binding Proteins, Female, Humans, Janus Kinase 2, Male, Middle Aged, Mutation, Polycythemia Vera, Primary Myelofibrosis, Proto-Oncogene Proteins, Repressor Proteins, Thrombocythemia, Essential

<p>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.</p>

Alternate JournalCancer Res
PubMed ID23066032
PubMed Central IDPMC5500294
Grant ListR01 HL082995 / HL / NHLBI NIH HHS / United States
T32 CA009173 / CA / NCI NIH HHS / United States
R01HL082995 / HL / NHLBI NIH HHS / United States
UL1 TR000439 / TR / NCATS NIH HHS / United States
R01 HL082946 / HL / NHLBI NIH HHS / United States
R01HL082946 / HL / NHLBI NIH HHS / United States