UTX, EZH2, and DNMT3A mutations identified in CMML. (A) In a cohort of 72 patients with CMML and AML-derived CMML, 2 somatic, inactivating UTX mutations were detected by sequencing. Four additional missense variants that could correspond to rare polymorphisms were identified. Profile of CN-LOH of X chromosome by SNP-A in one male patient with a UTX missense variant. Mutations/variants are denoted and relative to the UTX sequence NM_021140.1. The location of the TRP (tetratrico peptide repeat region) and JmjC (Jumonji C) domains is shown. (B) Identification of variations in EZH2-domain structure and positions of mutations in patients. All mutations were found in the SET domain or in close proximity. In 3 subjects mutations were identified along with CN-LOH7q encompassing EZH2 as shown for representative patient (SET indicates suppressor of variegation 3-9, enhancer of zeste and trithorax domain; SANT-DNA–binding domain in the SWI-SNF and ADA complexes, the transcriptional co-repressor N-CoR and TFIIIB). (C) Mutations identified in methyltransferase domain of DNMT3A in 7 patients with CMML and AML-derived CMML. Homozygous DNMT3A mutations were associated with CN-LOH2p involving DNMT3A. The location of the PWWP (a highly conserved proline-tryptophan-tryptophan-proline motif), PHD (plant homeodomain finger, a zinc-fingerlike motif), and MTase (methyltransferase) domains is shown. Missense mutations are indicated by black; frameshift by red, and nonsense mutations by green arrows.