In the context of the E2A-PBX1 model, the initiating lesion (an E2A-PBX1 fusion) is engineered into the mouse germline and results in increased self-renewal and impaired differentiation of B cell precursors. Subsequent mutations — that either occur spontaneously or are engineered into the mouse germline — lead to a complete block to B cell differentiation. Further mutations lead to increased proliferation or decreased apoptosis, resulting in an accumulation of leukemic B cell precursors. These additional mutations involve several overlapping pathways, including those involved in receptor tyrosine kinase (RTK) signaling, RAS signaling, and cell cycle progression. Mutations in several genes, including Jak1, Ptp11, Il17r, Nras, Kras, Ptpn11, Cdkn2a/b, and Tp53, were identified in the E2A-PBX1 model and were associated with disease progression. It should be noted that this order of mutations, while applicable for E2A-PBX1 mice with engineered mutations, is not necessarily invariant. For instance, an RTK mutation may precede a block to differentiation under certain circumstances. The general framework of this model is based on sequence data from leukemic patients (17, 28).