BCOR functional loss cooperates with other mutations to promote AML. Disruptive BCOR mutations that cause loss of the native protein or generate a truncated protein abrogate the capability of BCOR to bind PCGF1, thus preventing its interaction with KDM2B and the formation and recruitment to chromating of the enzymatic core. Thus, in hematopoietic stem and progenitor cells (HSPCs), the repressive activity of the complex is abrogated resulting into the expression of Hox and Cebp family genes. The occurrence of additional mutations (eg, DNMT3A and RUNX1) promotes the development of AML. Whether BCOR mutations precede or follow DNMT3A and RUNX1 mutations remains to be established.