Cancer and the Immune System CHAPTER 22 505 Normal cells Transformed cells gene. For example, avian leukosis virus(ALv) is a retrovirus that does not carry any viral oncogenes and yet is able to trans form B cells into lymphomas. This particular retrovirus has Retroviral been shown to integrate within the c-myc proto-oncogene, transduction which contains three exons. Exon 1 of c-myc has an unknown function; exons 2 and 3 encode the Myc protein Insertion of avl between exon i and exon 2 has been shown in some cases allow the provirus promoter to increase transcription of Mutagens, viruses. exons 2 and 3, resulting in increased synthesis of c-Myc. Expression radiation, and genetic A variety of tumors have been shown to express signifi- cantly increased levels of growth factors or growth-factor sential growth- Cellular oncogenes Growth-factor Expression (a) Chronic myelogenous leukemia Signal transducers trinuclear factors gelators of programmed ① Qualitatively altered, ell death hyperactive pro chromosome Quantitative alterations (gene amplification or translocation) or decreased levels FIGURE 22-2 Conversion of proto-oncogenes into oncogenes 22 involve mutation, resulting in production of qualitatively different gene products, or DNA amplification or translocation, resulting in increased or decreased expression of gene products. cer cells; these HSRs represent long tandem arrays of amplified 9q+ In addition, some cancer cells exhibit chromosomal trans (b)Burkitt's lymphor locations, usually the movement of a proto-oncogene fror one chromosomal site to another(Figure 22-3). In many cases of Burkitt's lymphoma, for example, c-myc is moved from its normal position on chromosome 8 to a position near the immunoglobulin heavy-chain enhancer on chro mosome 14. As a result of this translocation, synthesis of the c-Myc protein, which functions as a transcription factor Increases Mutation in proto-oncogenes also has been associated ∪cmyr with cellular transformation, and it may be a major mecha- nism by which chemical carcinogens or x-irradiation convert FIGURE 22-3 Chromosomal translocations in(a)chronic myeloge. a proto-oncogene into a cancer-inducing oncogene. For in- nous leukemia(CML) and(b)Burkitts lymphoma. Leukemic cells stance, single-point mutations in c-ras have been detected in from all patients with CML contain the so-called Philadelphia chromo- a significant fraction of several human cancers, including car- some, which results from a translocation between chromosomes 9 cinomas of the bladder, colon, and lung. Some of these muta- and 22. Cancer cells from some patients with Burkitts lymphoma ex- tions appear to reduce the ability of Ras to associate with hibit a translocation that moves part of chromosome 8 to chromo- GTPase-stimulating proteins, thus prolonging the growth- some 14. It is now known that this translocation involves c-myc,a activated state of Ras cellular oncogene. Abnormalities such as these are detected by band. pe Viral integration into the host-cell genome may in itself ing analysis of metaphase chromosomes. Normal chromosomes are rve to convert a proto-oncogene into a transforming onco- shown on the left, and translocated chromosomes on the right.cer cells; these HSRs represent long tandem arrays of amplified genes. In addition, some cancer cells exhibit chromosomal trans￾locations, usually the movement of a proto-oncogene from one chromosomal site to another (Figure 22-3). In many cases of Burkitt’s lymphoma, for example, c-myc is moved from its normal position on chromosome 8 to a position near the immunoglobulin heavy-chain enhancer on chro￾mosome 14. As a result of this translocation, synthesis of the c-Myc protein, which functions as a transcription factor, increases. Mutation in proto-oncogenes also has been associated with cellular transformation, and it may be a major mecha￾nism by which chemical carcinogens or x-irradiation convert a proto-oncogene into a cancer-inducing oncogene. For in￾stance, single-point mutations in c-ras have been detected in a significant fraction of several human cancers, including car￾cinomas of the bladder, colon, and lung. Some of these muta￾tions appear to reduce the ability of Ras to associate with GTPase-stimulating proteins, thus prolonging the growth￾activated state of Ras. Viral integration into the host-cell genome may in itself serve to convert a proto-oncogene into a transforming onco￾gene. For example, avian leukosis virus (ALV) is a retrovirus that does not carry any viral oncogenes and yet is able to trans￾form B cells into lymphomas. This particular retrovirus has been shown to integrate within the c-myc proto-oncogene, which contains three exons. Exon 1 of c-myc has an unknown function; exons 2 and 3 encode the Myc protein. Insertion of AVL between exon 1 and exon 2 has been shown in some cases to allow the provirus promoter to increase transcription of exons 2 and 3, resulting in increased synthesis of c-Myc. A variety of tumors have been shown to express signifi￾cantly increased levels of growth factors or growth-factor Cancer and the Immune System CHAPTER 22 505 Normal cells Transformed cells Proto–oncogenes Expression Retroviral transduction Mutagens, viruses, radiation, and genetic predisposition Cellular oncogenes Expression Viral oncogenes Essential growth– controlling proteins Growth factors Growth–factor receptors Signal transducers Intranuclear factors Regulators of programmed cell death 1 Qualitatively altered, hyperactive proteins 2 Quantitative alterations (gene amplification or translocation) resulting in increased or decreased levels of products FIGURE 22-2 Conversion of proto-oncogenes into oncogenes can involve mutation, resulting in production of qualitatively different gene products, or DNA amplification or translocation, resulting in increased or decreased expression of gene products. (a) Chronic myelogenous leukemia 9 22 Philadelphia chromosome (b) Burkitt's lymphoma 8 14 9 q+ 22 q– CH VH CH c–myc c–myc VH 8 q– 14 q+ FIGURE 22-3 Chromosomal translocations in (a) chronic myeloge￾nous leukemia (CML) and (b) Burkitt’s lymphoma. Leukemic cells from all patients with CML contain the so-called Philadelphia chromo￾some, which results from a translocation between chromosomes 9 and 22. Cancer cells from some patients with Burkitt’s lymphoma ex￾hibit a translocation that moves part of chromosome 8 to chromo￾some 14. It is now known that this translocation involves c-myc, a cellular oncogene. Abnormalities such as these are detected by band￾ing analysis of metaphase chromosomes. Normal chromosomes are shown on the left, and translocated chromosomes on the right