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 anal yzed both modes of inactivation of p15(INK4B) and p16(INK4A) in the ma jor types of adult and pediatric hematological malignancies. Hypermeth ylation of p15(INK4B), without alteration of p16(INK4A), was an almost universal finding in adult acute myelogenous leukemia, and occurred v ery frequently in adult acute lymphocytic leukemia and pediatric acute myelogenous leukemia and acute lymphocytic leukemia. In contrast, nei ther p15(INK4B) nor p16(INK4A) were inactivated in any stage of chroni c 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 reg ion methylation of these genes, as analyzed by a newly developed PCR m ethod. Remarkably distinct patterns of inactivation of p15(INK4B) and p16(INK4A) characterize different types of hematological malignancy, a nd alterations in these tumor suppressor genes are one of the most com mon alterations in hematological malignancies.