Distinct patterns of inactivation of p15(INK4B) and p16(INK4A) characterize the major types of hematological malignancies

Inactivation of the cyclin-dependent kinase inhibitors p16(INK4A) and p15(INK4B) are frequent alterations in neoplasia, often resulting from homozygous deletion or promoter region hypermethylation. We have analyzed both modes of inactivation of p15(INK4B) and p16(INK4A) in the major types of adult and pediatric hematological malignancies. Hypermethylation of p15(INK4B), without alteration of p16(INK4A), was an almost universal finding in adult acute myelogenous leukemia, and occurred very frequently in adult acute lymphocytic leukemia and pediatric acute myelogenous leukemia and acute lymphocytic leukemia. In contrast, neither p15(INK4B) nor p16(INK4A) were inactivated in any stage of chronic myelogenous leukemia. Hypermethylation of p16(INK4A), often without alterations of p15(INK4B), was found in non- Hodgkin's lymphoma and was much more frequent in cases with high-grade than low-grade histology. Enriched normal bone marrow stem cells had no detectable promoter region methylation of these genes, as analyzed by a newly developed PCR method. Remarkably distinct patterns of inactivation of p15(INK4B) and p16(INK4A) characterize different types of hematological malignancy, and alterations in these tumor suppressor genes are one of the most common alterations in hematological malignancies.