Nras^G12D and p53 deletion cooperate to induce a full-blown erythromyeloid leukemia by MEP transformation. (A) Mutations in molecules of RAS pathway were found in 17% of AML cases, whereas P53 mutations were found in 6% of AML cases. Moreover, comutation was found in 0.6% of AML cases, which were secondary or therapy-related AML with complex cytogenetics. (B) Nras^G12D KI mouse models presented an increase in hematopoietic stem cells (HSCs) and led to a CMML-like disease, whereas p53^−/− mice have no major role in myeloid hematopoietic compartments and led to T-ALL. In contrast, Nras^G12D p53^−/− mice presented HSC, Lin^–Sca1⁺c-Kit⁺ (LSK), multipotent progenitor (MPP), MEP, and granulocyte-monocyte progenitor (GMP) increases, leading to AML. The MEP was demonstrated to be the LIC. MP, myeloid progenitor; s-AML, secondary AML; t-AML, therapy-related AML.