Homozygous loss of the cyclin-dependent kinase 4-inhibitor (p16) gene in human leukemias

Abstract

Recently, it has been shown that the homozygous deletion of the cyclin- dependent kinase-4 inhibitor (CDK4I;p16) gene, which is mapped to chromosome 9p21, is frequently observed in a wide spectrum of human cancers, including leukemias. Therefore, the CDK4I gene is thought to be a putative tumor-suppressor gene. We report here that both alleles of the CDK4I gene were completely or partially deleted in human leukemia cells derived from both patients and established cell lines. Thirty-seven hematopoietic cell lines and samples from 72 patients with leukemias were examined for homozygous loss of the CDK4I gene locus by Southern blot analysis. We found that a part or the whole of the CDK4I gene was homozygously deleted in 14 of the 37 (38%) cell lines and 4 of 72 (6%) samples from leukemia patients, including 45 with acute myelocytic leukemia, 14 with acute lymphocytic leukemia (ALL), and 13 with chronic myelocytic leukemia in blastic crisis. In the cell lines, the homozygous deletion of the CDK4I gene was detected in a variety of cell lineages, whereas all 4 cases showing the homozygous deletion were confined to ALL. It should be noted that 2 of them had no cytogenetic abnormalities of chromosome 9. Our results suggest that loss of the CDK4I function may contribute to immortalization of human leukemia cells and play a causative role at least in development of human lymphocytic leukemias.

Comparative genomic hybridization reveals previously undescribed amplifications and deletions in the chronic myeloid leukemia-derived K-562 cell line

“…The notable deletion of 9p13=pter detected in the CGH analysis was consistent with cytogenetic findings of 9p loss (Table 1), and with homozygous deletion in K-562 cells of the cyclin-dependent kinase 4 inhibitor gene (CDKN2) p16, a candidate tumor suppressor gene located in chromosome band 9p21 (Ogawa et al, 1994;Sill et al, 1995). This finding is of interest for several reasons.…”

“…This finding is of interest for several reasons. First, molecular studies show that homozygous deletion of CDKN2 is associated with a wide spectrum of cancers, including lymphoid leukemias, and more particularly lymphoid, but not myeloid, blast crisis of CML (Ogawa et al, 1994(Ogawa et al, , 1995Serra et al, 1995;Sill et al, 1995). The K-562 cell line was established from a patient in myeloid blast crisis, and is unusual because it shows loss of both CDKN2, usually associated with lymphoid blast crisis, and TP53, regarded as specific for myeloid blast crisis (Imamura et al, 1994).…”

HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4.

“…The expression of pl6INK4A is in fact rather low in HTLV-1-infected T-cell lines and we could not demonstrate Tax binding to the endogenous pl6INK4A (data not shown). However, the frequent deletion of the p16INK4A gene in many uninfected T-cell lines (this study) and in T-cell leukemia (Ogawa et al, 1994) strongly indicates that pl6INK4A is critical for the normal regulation of T cells, at least at certain stages; thus its inactivation by deletion was observed so frequently after immortalization or transformation. Therefore, the functional inactivation of p16INK4A by Tax binding could play a critical role in immortalization or transformation of HTLV-1-infected T cells at certain stages.…”

Loss of heterozygosity on chromosome 9 in human breast cancer: Association with clinical variables and genetic changes at other chromosome regions

“…The highest deletion frequencies in the sporadic breast tumors in this study were observed with markers D9S156 (at 9p23-p22) and IFNA (at 9p22-p21). Homozygous LOH at IFNA and D9S162 are detectable in breast tumors, as has been reported in various other tumor types using comparative competition experiments, i.e., multiplex PCR amplification (Huang et al, 1994;Devlin et al, 1994;Merlo et al, 1994;Caldas et al, 1994;Ogawa et al, 1994;Cairns et al, 1995). However, homozygous deletions at D9S162 were not detectable in a few tumors.…”