Recurrently mutated or translocated genes with epigenetic function in AML
| Gene . | Epigenetic function . | Type of abnormalities described (percentage of AML) . | References . | Remarks . |
|---|---|---|---|---|
| DNMT3A | De novo DNA methylation | Mostly frameshifts; rare missense- and non-sense mutations (6-36%) | 7,11,,,,-16 | Associated with normal karyotype; may be associated with poor prognosis |
| TET2 | Conversion of 5-methylcytosine to 5-hydroxymethylcytosine | Frameshift, nonsense and missense mutations (8-27%) | 7,15,-17,18,,-21 | Mutually exclusive with IDH1/2 mutations |
| IDH1 and IDH2 | Enzymes that convert isocitrate to α-ketoglutarate (α-KG), a cofactor for TET2 | Missense mutations (5-16% for IDH1; 6-19% for IDH2) | 7,15,16,22,-24 | Mutually exclusive with TET2 mutations. Mutations result in production of 2-hydroxyglutarate, which inhibits TET2 function |
| CREBBP (CBP) | Histone lysine acetyltransferase | Rearrangements: fusion genes | 7,25 | Rare |
| KAT6A (MYST3/MOZ) | Histone lysine acetyltransferase | Rearrangements: fusion genes | 7,26 | Rare |
| EP300 (p300) | Histone lysine acetyltransferase | Rearrangements: fusion genes | 27,28 | Rare |
| HDAC2 and HDAC3 | Histone deacetylase | Missense mutations | 7 | Rare |
| KMT2A (MLL/MLL1) | H3K4 methyltransferase | Rearrangements: fusion genes (1-10%); partial tandem duplications (4-7%) | 7,15,16,29,,-32 | More than 50 fusion partners reported in acute leukemias |
| EZH2 | H3K27 methyltransferase, enzymatic component of PRC2 | Mutations (2%) | 7,33 | |
| NSD1 | H3K36 methyltransferase | Rearrangement involving NUP98 (2-5%) | 7,34,35 | |
| ASXL1 | Recruitment of PRC2 to target loci | Mostly frameshifts or nonsense mutations (3-25%) | 7,15,16,36,37,,,-41 | More common in elderly patients; poor prognosis particularly in association with RUNX1 mutations |
| ASXL2 | Homolog of ASXL1; function unknown | Mutations (23% of AML with RUNX1-RUNX1T1) | 42 | Mutually exclusive with ASXL1 mutations |
| JARID2 | Recruitment of PRC2 to target loci | Deletion in transformation of MDS or MPN to AML | 43 | |
| SUZ12 | Member of PRC2 | Missense mutations, insertions and deletions | 7,43,44 | Sporadically mutated in progression severe congenital neutropenia to AML; deleted in transformation MDS/MPN to AML |
| KDM5A (JARID1) | Histone lysine demethylase | Rearrangement involving NUP98 | 45 | 10% of pediatric acute megakaryoblastic leukemia |
| KDM6A (UTX) | Histone lysine demethylase | Missense mutations | 7,46 | Rare |
| Gene . | Epigenetic function . | Type of abnormalities described (percentage of AML) . | References . | Remarks . |
|---|---|---|---|---|
| DNMT3A | De novo DNA methylation | Mostly frameshifts; rare missense- and non-sense mutations (6-36%) | 7,11,,,,-16 | Associated with normal karyotype; may be associated with poor prognosis |
| TET2 | Conversion of 5-methylcytosine to 5-hydroxymethylcytosine | Frameshift, nonsense and missense mutations (8-27%) | 7,15,-17,18,,-21 | Mutually exclusive with IDH1/2 mutations |
| IDH1 and IDH2 | Enzymes that convert isocitrate to α-ketoglutarate (α-KG), a cofactor for TET2 | Missense mutations (5-16% for IDH1; 6-19% for IDH2) | 7,15,16,22,-24 | Mutually exclusive with TET2 mutations. Mutations result in production of 2-hydroxyglutarate, which inhibits TET2 function |
| CREBBP (CBP) | Histone lysine acetyltransferase | Rearrangements: fusion genes | 7,25 | Rare |
| KAT6A (MYST3/MOZ) | Histone lysine acetyltransferase | Rearrangements: fusion genes | 7,26 | Rare |
| EP300 (p300) | Histone lysine acetyltransferase | Rearrangements: fusion genes | 27,28 | Rare |
| HDAC2 and HDAC3 | Histone deacetylase | Missense mutations | 7 | Rare |
| KMT2A (MLL/MLL1) | H3K4 methyltransferase | Rearrangements: fusion genes (1-10%); partial tandem duplications (4-7%) | 7,15,16,29,,-32 | More than 50 fusion partners reported in acute leukemias |
| EZH2 | H3K27 methyltransferase, enzymatic component of PRC2 | Mutations (2%) | 7,33 | |
| NSD1 | H3K36 methyltransferase | Rearrangement involving NUP98 (2-5%) | 7,34,35 | |
| ASXL1 | Recruitment of PRC2 to target loci | Mostly frameshifts or nonsense mutations (3-25%) | 7,15,16,36,37,,,-41 | More common in elderly patients; poor prognosis particularly in association with RUNX1 mutations |
| ASXL2 | Homolog of ASXL1; function unknown | Mutations (23% of AML with RUNX1-RUNX1T1) | 42 | Mutually exclusive with ASXL1 mutations |
| JARID2 | Recruitment of PRC2 to target loci | Deletion in transformation of MDS or MPN to AML | 43 | |
| SUZ12 | Member of PRC2 | Missense mutations, insertions and deletions | 7,43,44 | Sporadically mutated in progression severe congenital neutropenia to AML; deleted in transformation MDS/MPN to AML |
| KDM5A (JARID1) | Histone lysine demethylase | Rearrangement involving NUP98 | 45 | 10% of pediatric acute megakaryoblastic leukemia |
| KDM6A (UTX) | Histone lysine demethylase | Missense mutations | 7,46 | Rare |
Sporadic mutations from TCGA7 extracted using COSMIC (http://cancer.sanger.ac.uk/).
MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; PRC, polycomb repressor complex.