Our results delineate a new mechanism by which a specific subset of DP T-cells, with a high Notch3 and CXCR4 co-expression and an elevated proliferation rate, are forced to egress from the thymus and fit to rapidly colonize BM and possibly peripheral organs (i.e., the spleen) during T-ALL progression. The gene discussed is NOTCH3; the disease is acute lymphoblastic leukemia.