Clonal evolution of myeloid malignancies with loss-of-function mutations of EZH2. Loss-of-function mutations of Enhancer of Zeste Homolog 2 (EZH2) are thought to be early events in clonal evolution of myeloid malignancies. Studies have shown that mutations of EZH2 can precede the acquisition of mutations of other epigenetic regulators such as Ten-Eleven Translocation Methylcytosine Dioxygenase 2 (TET2). Signaling gene mutations usually occur later in disease evolution. Additional Sex Combs Like 1 (ASXL1) mutations have been shown to precede the acquisition of EZH2 mutations [20,60,74]. Unlike EZH2 mutations, ASXL1 mutations have been shown to be involved in age-related clonal hematopoiesis (ARCH) [75,76,77], suggesting loss-of-function EZH2 mutations are highly oncogenic and frequently involved in leukemia initiation. HSC: Hematopoietic stem cell; JAK2: Janus Kinase 2; KRAS: Kirsten Rat Sarcoma Viral Oncogene Homolog; SETBP1: SET-binding Protein 1.