Loss of the INK4A Locus Accelerates tal1/scl-Induced Leukemia in Mice.

Tal1/scl, a basic helix-loop-helix (bHLH) transcription factor essential for hematopoiesis and vasculogenesis, is also found misexpressed in patients with T cell acute lymphoblastic leukemia (T-ALL). In our mouse model of tal1/scl-induced disease, mice develop T cell leukemia after a long latency, suggesting that additional mutations are required for leukemogenesis. In T-ALL patients, the INK4a locus, which encodes both p14^ARF and p16^INK4a, is often found mutated or methylated, suggesting that loss of p16^INK4A/p14^ARF expression contributes to the development of T-ALL. Similarly, we fail to detect p16^INK4A/p19^ARF expression in our mouse tal1/scl leukemic cells. To determine if the loss of INK4a cooperates with tal1/scl to induce leukemia, we mated our tal1/scl transgenic mice to INK4a −/− mice to generate a cohort of tal1/scl/INK4a+/− mice. Mice heterozygous for INK4a are healthy and are not predisposed to the development of leukemia. In contrast, tal1/scl/INK4a+/− mice develop T cell leukemia at an accelerated rate, within a median survival period of 110 days, compared to a median survival of 352 days for the tal1/scl transgenic mice, which are wild type with respect to INK4a. Taken together, these data suggest that mutation of the INK4a locus contributes to tal1/scl-mediated leukemogenesis in mice, similar to the widespread deletion of the INK4a/ARF locus observed in TAL1/SCL-expressing human leukemia (Ferrando, 2002). BrdU labeling of preleukemic tal1/scl thymocytes reveals a 41% increase in the percentage of thymocytes in S phase of the cell cycle, suggesting that tal1/scl may stimulate cell cycle progression. In contrast to wild type thymocytes which exhibit 14.5% (±1.5) of cells in S phase, 24.5% (± 2.9) of preleukemic tal1/scl thymocytes are found in S phase (p<0.05, n=4). Moreover, an increase in the sub-G1 population is also observed in the tal1/scl preleukemic thymus. Preliminary cell cycle analysis of tal1/scl/INK4a−/− thymocytes reveals a decrease in the sub-G1 population, suggesting that the absence of the INK4a locus may contribute to tal1/scl leukemogenesis, in part, by inhibiting the tal1/scl-induced apoptosis.