PcG proteins represses key lineage-commitment genes. Accordingly, loss of EZH2 associated with deletion of chromosome 7 is accompanied by significant up-regulation of the key megakaryocyte differentiation driver FLI1, and decreased expression of ASXL1 is accompanied by significant up-regulation of the monocyte differentiation-driver PU.1. (A) Decreased EZH2 expression produced by chromosome 7 loss (Del. 7) is associated with significant up-regulation of FLI1 and thrombopoietin receptor (TPOR). N.Cyto, n = 106; Del. 7, n = 18. Gene expression data extracted from GSE6891. Wilcoxon test. Box plot boundaries = interquartile range; horizontal line = median; + = mean; whiskers = range of values; small boxes = out-lying values. (B) In a normal hematopoietic hierarchy, ASXL1 expression is lowest in colony forming unit monocyte (CFU-M) cells compared with CFU-granulocyte (CFU-G), granulocyte monocyte progenitors (GMP), common myeloid progenitors (CMP), CD38-/CD34+ hematopoietic stem cells (HSC2) and CD133+/CD34dim HSC (HSC1). Gene expression data extracted from GSE24759. (C) In AML with normal cytogenetics, lower ASXL1 expression (ASXlo, n = 53) is significantly associated with higher expression of PU.1 and macrophage colony stimulating factor receptor (MCSFR; higher ASXL1 expression = ASXhi, n = 53). Wilcoxon test. (D) Evolution of MDS/MPD into AML is associated with lineage-restriction of self-renewing leukemia initiating cells,^8-10  a differentiation-transition that is favored by EZH2 or ASXL1 inactivation. Mutations in key hematopoietic transcription factor genes such as RUNX1 or CEBPA impair progressive maturation of lineage-committed cells, a critical element in transformation into AML. MEP indicates megakaryocyte-erythroid progenitors.