Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms
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Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms. / Nischal, 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; Verma, Amit.
In: CANCER RES, Vol. 73, No. 3, 01.02.2013, p. 1076-85.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms
AU - Nischal, Sangeeta
AU - Bhattacharyya, Sanchari
AU - Christopeit, Maximilian
AU - Yu, Yiting
AU - Zhou, Li
AU - Bhagat, Tushar D
AU - Sohal, Davendra
AU - Will, Britta
AU - Mo, Yongkai
AU - Suzuki, Masako
AU - Pardanani, Animesh
AU - McDevitt, Michael
AU - Maciejewski, Jaroslaw P
AU - Melnick, Ari M
AU - Greally, John M
AU - Steidl, Ulrich
AU - Moliterno, Alison
AU - Verma, Amit
PY - 2013/2/1
Y1 - 2013/2/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Azacitidine
KW - Cell Line, Tumor
KW - DNA Methylation
KW - DNA-Binding Proteins
KW - Female
KW - Humans
KW - Janus Kinase 2
KW - Male
KW - Middle Aged
KW - Mutation
KW - Polycythemia Vera
KW - Primary Myelofibrosis
KW - Proto-Oncogene Proteins
KW - Repressor Proteins
KW - Thrombocythemia, Essential
U2 - 10.1158/0008-5472.CAN-12-0735
DO - 10.1158/0008-5472.CAN-12-0735
M3 - SCORING: Journal article
C2 - 23066032
VL - 73
SP - 1076
EP - 1085
JO - CANCER RES
JF - CANCER RES
SN - 0008-5472
IS - 3
ER -