Localization of a lymphocyte-specific protein tyrosine kinase gene (lck) at a site of frequent chromosomal abnormalities in human lymphomas.

Abstract

The murine Ick gene is closely related to a family of cellular protooncogenes and encodes a lymphocytespecific, membrane-associated protein tyrosine kinase. We and others have demonstrated that the Ick gene is rearranged and overexpressed in the murine lymphoma LSTRA, most likely as a result of the insertion of Moloney murine leukemia virus DNA immediately adjacent to the gene. We now report that the Ick gene is located at the distal end of murine chromosome 4 and on human chromosome 1 at position lp32-35 near a site of frequent structural abnormalities in human lymphomas and neuroblastomas. These results raise the possibility that structural alteration of the ick gene through chromosomal rearrangement may contribute to transformation in human malignant disease.At least twelve genes encoding protein tyrosine kinases have been implicated in neoplastic transformation in mammalian cells (1, 2). Broadly speaking, characterized protein tyrosine kinase genes can be divided into two subfamilies. The first -encodes a group of cell-surface receptors that mediate mitogenesis. Ligands for these receptors are in three cases known, the epidermal growth factor (EGF) receptor (3), the insulin receptor (4), and the colony-stimulating factor 1 (CSF-1) receptor (5), while two other members of this subfamily encode receptor structures for which ligands are at present unidentified, neu (6, 7) and trk (8). A second subfamily of protein tyrosine kinase genes encodes a group of proteins that are typically membrane-associated but which lack recognizable transmembrane domains, for example abl, fgr, src, and lck** (1, 2, 9, 10). The protein tyrosine kinase oncogenes were originally identified as components of acutely transforming retroviruses or through transformation of cultured fibroblasts via transfection of tumor DNA (1, 2). In at least one case, the t(9;22) translocation of human chronic myelogenous leukemia, activation of a protein tyrosine kinase protooncogene (abi) results from a spontaneous chromosomal rearrangement (11,12). Thus protein tyrosine kinases may in some cases be involved in the specific chromosomal abnormalities frequently detected in human and murine neoplasia.The murine Ick gene encodes a lymphocyte-specific, membrane-associated protein tyrosine kinase of unknown function. We and others have demonstrated that this gene is rearranged and overexpressed in the murine lymphoma LSTRA, most likely as a result of insertion of Moloney murine leukemia virus sequences immediately upstream of the gene (9, 10). We now report that the Ick gene is located on human chromosome 1 at position 1p32-35 in a site of frequent structural abnormalities in human lymphomas and neuroblastomas. These results suggest that structural alteration of the lck gene through chromosomal rearrangement may occasionally contribute to transformation in human malignant disease. (14). Hybridization of the lck probe to mitotic chromosomes was performed by a modification of the method of Harper and Saunders (15). Briefly, chromosome slide preparatio...

Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin.

“…(Fig. 2), avian c-src (exon 3) and murine Ick (33,39). The numbers reflect the codon position from the initiating methionine in each case.…”

A Constitutively Active Lck Kinase Promotes Cell Proliferation and Resistance to Apoptosis through Signal Transducer and Activator of Transcription 5b Activation

“…The oncogenic properties of Lck in vivo was first shown by the development of thymic tumors in transgenic mice that overexpress Lck (3). In humans, the lck gene is located at a site of frequent chromosomal abnormalities associated with lymphomas (4). Aberrant Lck expression and kinase activity have also been implicated in the pathogenesis of both lymphoid and nonlymphoid malignancies (5,6).…”

Structure of the murine lck gene and its rearrangement in a murine lymphoma cell line.

“…The Ick gene is predominantly expressed in thymocytes and in resting T cells and at lower levels in some B-cell lines (18). Furthermore, the Ick gene is specifically implicated in the pathogenesis of lymphoid malignancy by virtue of its rearrangement and overexpression in two independently obtained murine lymphoma cell lines, LSTRA and Thy-19 (6,18,37), and by its localization at a site of frequent chromosomal abnormalities (lp32-35) in human non-Hodgkin lymphomas (15). The gene is also overexpressed in some human colon and lung tumors (34 (22).…”