p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice

Abstract

Analysis of the INK4A/ARF locus in human T-ALL patients revealed frequent deletions in exon 2, the exon common to both p16^INK4A and p14^ARF. Other studies have described selective deletion of exon 1β of p14^ARF or methylation of the p16^INK4A promoter. Therefore, it is unclear from these studies whether loss of p16^INK4A and/or p14^ARF contributes to the development of T-ALL. To elucidate the relative contribution of the ink4a/arf locus to T-cell leukemogenesis, we mated our tal1 transgenic mice to ink4a/arf−/−, p16^ink4a−/−, and p19^arf−/− mice and generated tal1/ink4a/arf+/−, tal1/p16^ink4a+/−, and tal1/p19^arf+/− mice. Each of these mice developed T-cell leukemia rapidly, indicating that loss of either p16^ink4a or p19^arf cooperates with Tal1 to induce leukemia in mice. Preleukemic studies reveal that Tal1 expression stimulates entry into the cell cycle and thymocyte apoptosis in vivo. Interestingly, mice expressing a DNA-binding mutant of Tal1 do not exhibit increases in S phase cells. The S phase induction is accompanied by an increase in thymocyte apoptosis in tal1 transgenic mice. Whereas apoptosis is reduced to wild-type levels in tal1/ink4a/arf−/− mice, S phase induction remains unaffected. Thus, Tal1 stimulates cell cycle entry independent of the ink4a/arf locus, but its ability to induce apoptosis is Ink4a/Arf-dependent.