Collectively, our findings support a model in which multiple small defects in a network of factors that regulate B-cell maturation (such as Pax5, Cblb, Zfp423, Foxp1, and Stat5b) together with activation/inactivation of oncogenes/tumor suppressor genes (such as the JAK/STAT signaling pathway and p53) cooperate with Etv6-RUNX1; Pax5+/− to result in the development B-ALL. Here, RUNX1 is linked to acute lymphoblastic leukemia.