Table 1. Epigenetically implicated mutations in myeloid malignancies.

Mutations	Chromosome location	Mutational frequency	Pathogenetic relevance
TET2 mutations involve several exons25, 146	4q24	PV ∼16%146 ET ∼5%146 PMF ∼17%146 BP-MPN ∼17%146 AML ∼20%57 MDS ∼26%58 CMML ∼51%56 SM ∼29%52 RARS-T ∼26%59	TET proteins catalyze conversion of 5mC to 5hmC, which favors demethylated DNA. Both TET166 and TET267 display this catalytic activity. IDH and TET2 mutations might share a common pathogenetic effect, which might include abnormal DNA hypermethylation and impaired myelopoiesis.
ASXL1 exon 12 mutations26	20q11.1	ET ∼3%72 PMF ∼13%39 BP-MPN ∼18%39 AML ∼11%76 MDS ∼11%26 CMML ∼43%26	Wild-type ASXL1 is needed for normal hematopoiesis69 and might be involved in coactivation of transcription factors and transcriptional repression.70, 71
IDH1/IDH2 exon 4 mutations35	2q33.3/15q26.1	PV ∼2%35 ET∼1%35 PMF ∼4%35 BP-MPN ∼20%35 AML ∼14%87 MDS ∼5%55	IDH mutations induce loss of activity for the conversion of isocitrate to 2-KG and gain-of-function in the conversion of 2-KG to 2-HG.81, 82 2-HG might be the mediator of impaired TET2 function in cells with mutant IDH expression.68
EZH2 mutations involve several exons41	7q36.1	PV ∼3%41 PMF ∼7%39 MDS ∼6%41, 97 CMML ∼13%41 aCML ∼13%41 HES/CEL ∼3%41	Wild-type EZH2 is part of a histone methyltransferase (polycomb-repressive complex 2 associated with H3 Lys-27 trimethylation). MPN-associated EZH2 mutations might have a tumor-suppressor activity,41 which contrasts with the gain-of-function activity for lymphoma-associated EZH2 mutations.93

Abbreviations: aCML, atypical chronic myeloid leukemia, BCR-ABL1-negative; AML, acute myeloid leukemia; ASXL1, additional sex comb-like 1; BP-MPN, blast phase myeloproliferative neoplasm; CMML, chronic myelomonocytic leukemia; CP-MPN, chronic phase MPN; ET, essential thrombocythemia; EZH2, enhancer of zeste homolog 2; HES/CEL, hypereosinophilic syndrome/chronic eosinophilic leukemia; IDH, isocitrate dehydrogenase; MDS, myelodysplastic syndrome; PMF, primary myelofibrosis; PV, polycythemia vera; RARS-T, refractory anemia with ring sideroblasts; SM, systemic mastocytosis; TET2, TET oncogene family member 2; 2-HG, 2-hydroxyglutarate; 2-KG, 2-ketoglutarate; 5hmC, 5-hydroxymethylcytosine; 5mC, 5-methylcytosine.

MF includes both PMF and post-ET/PV myelofibrosis.