LOSS OF THE CYCLIN-DEPENDENT KINASE 4-INHIBITOR (P16-MTS1) GENE IS FREQUENT IN AND HIGHLY SPECIFIC TO LYMPHOID TUMORS IN PRIMARY HUMAN HEMATOPOIETIC MALIGNANCIES

The cyclin-dependent kinase 4-inhibitor (CDK41; p16; or (MTS1) gene ha s been proposed as a candidate for a tumor-suppressor gene located in chromosome 9p21, a frequently deleted region in a wide spectrum of hum an cancers, including leukemias. Recent studies disclosed that it was frequently deleted or mutated in a variety of primary human cancers, i ncluding acute lymphoblastic leukemia. The purpose of this study is to figure out the precise manners and frequencies of p16 gene inactivati on in diverse hematopoietic tumor types and thus to clarify its signif icance in development of human hematopoietic malignancies. A total of 410 tumor specimens from patients with primary hematopoietic malignanc ies were examined for deletions of the p16 gene as well as the neighbo ring p15 gene and the nearby interferon alpha gene by Southern blot an alysis. Tumor-specific mutations or small deletions of the p16 gene we re also studied in 74 patients using single-strand conformation polymo rphism analysis and direct sequencing. Loss of the p16 gene was most f requently observed among the three genes examined and was found in 59 of the 410 patients: 2 of 134 with acute myelocytic leukemia, 41 of 10 5 with acute lymphocytic leukemia, 2 of 15 with chronic lymphocytic le ukemia, 5 of 14 with adult T-cell leukemia, 4 of 33 with non-Hodgkin's lymphoma, 3 of 8 with mixed-lineage leukemia, and 2 of 61 with chroni c myelocytic leukemia. In 16 of the 59 patients, the p16 deletions occ urred due to rearrangements within the small region between the p15 ex on 2 and the p16 exon 2. Tumor-specific mutations or small deletions o f the p16 gene were not detected in the 74 patients examined, includin g 12 of 14 patients with hemizygous deletions of the gene. Loss of the p16 gene is frequent in and highly specific to lymphoid malignancies (54 of 183 [30%] in lymphoid tumors v 2 of 219 [1%] in myeloid tumors; P <.0001). The deletion analyses strongly suggest that the pig gene i s a tumor-suppressor gene located in chromosome 9p21 that is involved in development of human lymphoid tumors. Gene deletions but not minute mutations should be the predominant mechanism of p16 gene inactivatio n in these types of tumors. (C) 1995 by The American Society of Hemato logy.