Showing papers by "Carlo M. Croce published in 1989"

Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma.

Abstract: We analyzed a t(1;14)(p32;q11) chromosomal translocation in a human lymphohemopoietic stem cell line derived from a patient with acute T-lymphoblastic leukemia. The chromosomal joining on the 1p+ chromosome occurred at the T-cell receptor delta diversity (D delta 2) segment, and the reciprocal chromosomal joining on the 14q- chromosome occurred at the T-cell delta diversity segment D delta 1. The involvement of delta diversity segments at the translocation junctions suggests that the translocation occurred during an attempt at D delta 1-D delta 2 joining in a stem cell. The segment of chromosome 1 at band p32, adjacent to the chromosomal breakpoint, encodes a transcriptional unit designated TCL5 (T-cell leukemia/lymphoma 5). The differential expression of the TCL5 RNA transcripts in this lymphohemopoietic stem cell line relative to several other T- and B-cell lines suggests that TCL5 gene expression is an integral event in the pathogenesis of the T-cell leukemia. Rearrangement of the TCL5 locus in a human melanoma cell line carrying a del(1p32) further implies that the TCL5 gene may play a role in malignant transformation.

Activation of MYC in a masked t(8;17) translocation results in an aggressive B-cell leukemia

Abstract: We have analyzed the oncogene rearrangements involving BCL2 and MYC in the leukemia cells of a patient with an aggressive prolymphocytic leukemia that had an abnormal karyotype including a t(14;18) translocation and a chromosome 17q+. Molecular analysis showed that BCL2 was rearranged in the major breakpoint cluster region and had joined into the immunoglobulin heavy chain gene as in follicular lymphoma. Cloning and sequence analysis of the rearranged MYC gene revealed that MYC was truncated at the Pvu II site at the end of the first exon of MYC and had joined into the regulatory elements of a gene that we called BCL3 (B-cell leukemia/lymphoma 3). The BCL3 locus was mapped to chromosome 17 band q22. We found BCL3 transcribed as a message of 1.7 kilobases in many hematopoietic cell lines representing all hematopoietic lineages. In the patient's leukemia cells, the truncated MYC gene was highly expressed under the influence of BCL3 regulatory elements, leading to an aggressive B-cell leukemia that presumably had been derived from an indolent lymphoma carrying a rearranged BCL2 gene.

Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21.

Abstract: Filaggrins are an important class of intermediate filament-associated proteins that interact with keratin intermediate filaments of terminally differentiating mammalian epidermis. They show wide species variations and their aberrant expression has been implicated in a number of keratinizing disorders. We have isolated a cDNA clone encoding human filaggrin and used this to demonstrate that the human gene encodes a polyprotein precursor containing numerous tandem filaggrin repeats. This structure is similar to that of mouse; however, the human filaggrin repeat is much longer (972 base pairs; 324 amino acids) and shows little sequence homology to the mouse protein. Also, data presented here reveal that the human filaggrin repeats show considerable sequence variations; such polymorphism is not found in the mouse. Furthermore, chromosomal mapping data revealed that the human gene is located at 1q21, indicating that the polymorphism is confined to a single locus. By peptide mapping, we define a short linker sequence within the human filaggrin repeat that is excised by proteolysis to yield functional molecules. Finally, we show by in situ hybridization that human filaggrin precursor gene expression is tightly regulated at the transcriptional level in terminally differentiating epidermis and that this represents a useful system in which to study intermediate filament-intermediate filament-associated protein interactions as well as disorders of keratinization.

Variant translocation of the bcl-2 gene to immunoglobulin lambda light chain gene in chronic lymphocytic leukemia

Abstract: The bcl-2 gene has been identified as a gene directly involved in the consistent chromosome translocation t(14;18), which is found in approximately 90% of human follicular lymphoma cases, and is a prime candidate for the oncogene playing a crucial role in follicular lymphomagenesis. In this paper, we describe a case of chronic lymphocytic leukemia showing the juxtaposition of the bcl-2 gene on chromosome 18 to immunoglobulin lambda light chain (Ig lambda) gene on chromosome 22 in a head-to-head configuration. Sequencing analysis of the joining site of the bcl-2 gene and Ig lambda gene has shown that the breakpoint is within the 5' flanking region of the bcl-2 gene and about 2.2 kilobases 5' to the joining segment of Ig lambda locus in a germ-line configuration. The extranucleotide, commonly appearing at the joining site of the t(14;18) translocation involving the IgH locus, is absent from the joining site of bcl-2 and Ig lambda. The lack of extranucleotide suggests that the juxtaposition of the bcl-2 and Ig lambda genes occurred during physiological rearrangement of the Ig lambda gene since it has been shown that the rearrangement of the Ig lambda locus is not accompanied by extranucleotides.

Lineage-specific gene rearrangement/deletion: a nonconservative model.

Abstract: For the lymphocytic descendants of the hematopoietic differentiation pathway, characteristic gene rearrangements result in deletions of significant portions of chromosome regions specifying lymphocyte-specific gene products on either or both chromosomes of each involved pair. Molecular mechanisms facilitating the rearrangement/deletion events have been elegantly and fruitfully elaborated in the years since the first documentation of their occurrence by Hozumi and Tonegawa (N. Hozumi and S. Tonegawa, Proc. Natl. Acad. Sci. USA, 73: 3628–3632, 1976). Numerous genetic phenomena observed in experiments or the literature suggest to us that specific genome rearrangement/deletion may be characteristic of and necessary for many, perhaps all, differentiating lineages. Thus we propose that on the way to terminal differentiation, cells within a particular lineage must rearrange specific chromosome regions characteristic for that lineage in order to switch off or on, perhaps concomitantly, requisite genes for that differentiation program. Such rearrangements and their ensuing deletions may have been undetected cytogenetically because of small size and/or because normal terminally differentiated cells do not enter mitosis. However, footprints of these rearrangements, most likely in aberrant form, may be preserved in preneoplastic cells and cancer cells of various lineages which exhibit characteristic deletions. An understanding of the cellular recombinational machinery involved in normal physiological genome rearrangements such as we propose may clarify some puzzling aspects of current theories concerning retinoblastoma, Wilms' tumor, and other “deletion syndromes” and the role of parental genome imprinting [B. M. Cattanach and M. Kirk, Nature (Lond.), 315: 496–498, 1985; C. Sapienza et al. , Nature (Lond.), 328: 251–254, 1987; D. Solter, Annu. Rev. Genet., 22: 127–146, 1988]. The recombinatorial activity, when inappropriately expressed in dividing cells ( i.e. , cells which should be terminally differentiated but are still cycling for various reasons) could be responsible for such diverse phenomena as large deletions; chromosomal translocations into commonly deleted regions; amplicons; apparent nonrandom chromosome integration of viral genomes such as hepatitis B, human papilloma virus, papovaviruses, and retroviruses; and the observation of fragile sites. It could explain why these various phenomena often involve the same restricted regions of the genome. Some clues and consequences integral to the proposal are discussed. Among the most important conclusions are: hemizygous deletions in different cellular lineages discovered in many tumors as footprints of hypothetical normal physiological deletions will show where in the genome to look for the normal rearrangements in terminally differentiated cells, leading to eventual dissection of mechanisms involved in development and differentiation; if evidence for lineage-specific gene rearrangement is forthcoming, careful consideration must be given to the source of tissues to serve as the germ line in constructing the map and sequence of the human genome.

Deregulated BCL2 expression enhances growth of a human B cell line.

Abstract: The BCL2 (B cell lymphoma/leukemia -2) and C-MYC oncogenes become activated by chromosomal translocations involving the immunoglobulin heavy chain locus in human follicular lymphomas and Burkitt lymphomas, respectively. Though much is known about the biological actions of C-MYC, little information is available concerning the functions of BCL2, particularly in human B cells. Using a gene transfer approach we contrasted the effects of deregulated BCL2 and C-MYC expression in a human EBV-immortalized B cell line GM607B. Both BCL2 and C-MYC enhanced the ability of GM607B cells to grow in reduced serum and in limiting dilution cultures. These findings provide direct evidence that BCL2 can alter the growth characteristics of human B lymphocytes, thus strengthening arguments for its role in the pathogenesis of human lymphomas.