We assayed the capacity of tumor promoters to induce human T-cell leukemia/lymphoma virus (HTLV) structural proteins p19 and p24 from the HTLV genome-carrying adult T-cell leukemia (ATL) cell lines, MT-1 and KH-2Lo, and fresh ATL cells.
We reported previously that an N-terminally truncated insulinlike growth factor I receptor (IGFR) fused to avian sarcoma virus UR2 gag p19 had a greater transforming potential than did the native IGFR, but it failed to cause tumors in vivo.
In particular, the experiments on tumor cell transfection with constructions containing either a sense or antisense mts1 sequence under a strong promoter/enhancer element show the direct dependence of the metastatic phenotype on the expression of the mts1 gene at least in some systems.
These results suggested that the MTS1/CDK4I gene is a tumor suppressor the inactivation of which plays an important role during carcinogenesis of the squamous cell type of esophageal carcinoma.
Esophageal cancer is one primary human tumor in which MTS1 constitutes an apparent target of heterozygous or homozygous deletions occurring at chromosome 9p21.
Homozygous deletions of p16INK4 were detected in several cell lines, but intragenic mutations of this gene were unusual in either cell lines or primary tumors.
The low frequency of MTS1 mutations in primary astrocytomas with allelic 9p loss suggests that MTS1 may be more important for in vitro than in vivo astrocytoma growth, and that another 9p tumor suppressor gene may be involved in astrocytoma formation in vivo.
Frequent homozygous deletions of this gene have been documented in cell lines derived from different types of tumors, including breast tumors, suggesting that CDKN2 is a tumor suppressor gene involved in a wide variety of human cancers.
Using a Southern blot approach, deletions of MTS1 (multiple tumor-suppressor gene 1) and MTS2 (multiple tumor-suppressor gene 2) candidate tumor-suppressor genes have been studied in primary neoplastic cells from 55 acute lymphoblastic leukemia (ALL) patients.
Furthermore, in two cases abnormalities in the MTS1/CDK4I gene were identical in cells derived from metastatic tumours as compared to cells derived independently from the corresponding primary tumour.
Recently, the inhibitor of cyclin-dependent kinase 4 (CDK4I; also known as p16INK4, multiple tumor suppressor 1, or CDKN2 gene) has been mapped to 9p21 and shown to be mutated or deleted in a large fraction of cell lines derived from many tumor types, including melanoma, suggesting that this gene could be a melanoma suppressor gene.
These results suggest that mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a.
These results: (i) demonstrate that the phosphorylase deficiency is distributed among almost all the most important human cancers; (ii) confirm and extend the tumor types were p16INK4 gene inactivation is observable and (iii) suggest that deletions at 9p21 (in humans) or at syntenic chromosomes (in other species) might represent a general mechanism of p16INK4 gene loss of function and possibly, in turn, of cancer development and/or progression.
The apparent lack of other mutations in p16 and p15 in the tumors with loss of heterozygosity leaves open the possibility of an unidentified gene in this region that may function as a tumor suppressor.
The p15 (MTS2) and p16 (CDKN2/MTS1) genes located on chromosome 9p have been implicated as candidate tumor-suppressor genes in several types of tumors.
It was not possible, using multiplex PCR with primers for MTS1 and D9S196, a chromosome 9q marker, to demonstrate deletions of MTS1 in 59 primary non-astrocytic tumors.
We conclude that hemizygous or homozygous deletions of the CDKN2 gene occur at high frequency in T-ALL and at low frequency in B-lineage ALL, supporting the role of this gene as a tumour suppressor, especially in T-ALL.