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2013 ; 73
(3
): 1076-85
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Methylome profiling reveals distinct alterations in phenotypic and mutational
subgroups of myeloproliferative neoplasms
#MMPMID23066032
Nischal S
; Bhattacharyya S
; Christopeit M
; Yu Y
; Zhou L
; Bhagat TD
; Sohal D
; Will B
; Mo Y
; Suzuki M
; Pardanani A
; McDevitt M
; Maciejewski JP
; Melnick AM
; Greally JM
; Steidl U
; Moliterno A
; Verma A
Cancer Res
2013[Feb]; 73
(3
): 1076-85
PMID23066032
show ga
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.