Schematic representation of BCOR knockout and double compound mouse models. The presence of different partner mutations in the Bcor conditional knockout mouse model (BcorΔ4/Y, BcorΔ9-10/Y, BcorΔ8-10/Y) variably affects the severity and penetrance of the disease phenotype. In particular, BcorΔ4/Y,p53−/− mice exacerbate the T-ALL developed in BcorΔ4/Y mice. Compound mutant mice carrying BcorΔ9-10/Y,Tet2−/− mutations develop a progressive lethal MDS. Compound mice comutated for BcorΔ9-10/Y, and KrasG12D develop AML, and mice comutated for BcorΔ8-10/Y and Dnmt3aΔ19-20 develop acute erythroid leukemia (AEL). An approach of multiplex genome editing of primary mouse hematopoietic stem and progenitor cell transplanted in a clustered regularly interspaced short palindromic repeat (CRISPR)-cas9 mice compound demonstrates that comutations of Bcor, Trp53 plus Dnmt3a or Rb1 or Nfix results in AEL. In contrast, the contemporary comutations of Bcor, Dnmt3a, Trp53, and tet2 result in T-ALL, and the contemporary comutations of Bcor, tet2 and Sf3b3 lead to B-ALL.