Allelic loss and promoter hypermethylation of the p15^INK4b gene features in mouse radiation-induced lymphoid – but not myeloid – leukaemias

Abstract

Mouse radiation-induced acute myeloid leukaemias (AMLs) which arose in a (CBA/H × C57BL/6) genetic background have a 45% incidence of loss of heterozygosity (LOH) on chromosome 4. Frequent chromosome 4 LOH in mouse radiation-induced (C57BL/6 × RF/J) thymic lymphomas (TLs) is associated with promoter/exon 1 region hypermethylation of the remaining p15^INK4b and p16^INK4a alleles, so this may be common to mouse radiation myeloid and lymphoid leukaemogenesis. We addressed the question of p15^INK4b/p16^INK4a/p19^ARF gene promoter hypermethylation in radiation-induced AMLs by comparison to TLs which arose in a similar (C57BL/6 × CBA/H) genetic background as a consequence of the same initiating dose of 3 Gy X-rays. Only one homozygous deletion was detected in the ∼100 leukaemias analysed. p15^INK4b gene promoter/exon 1 hypermethylation was readily detected (21%) in the lymphoid but not myeloid (3.1%) leukaemias, and p16^INK4a and p19^ARF gene promoter/exon 1 methylation was rare (<3%) in both. thus, allelic loss and promoter hypermethylation of the p15^INK4b gene is particular to radiation-induced lymphoid leukaemias and is independent of p16^INK4a and p19^ARF gene promoter/exon 1 hypermethylation.