506 PARt IV The Immune System in Health and Disease receptors. Expression of the receptor for epidermal growth by mating the bd-2 transgenic mice with myc*transgenic factor, which is encoded by c-erbB, has been shown to be mice. These mice develop leukemia very rapidly amplified in many cancer cells And in breast cancer, increased synthesis of the growth-factor receptor encoded by c-neu has Tumors of the Immune System been linked with a poor prognosis. of the immune system are classified as lymphomas The Induction of Cancer Is a Multiste mias. Lymphomas proliferate as solid tumors within Process hoid tissue such as the bone marrow, lymph nodes, or thymus; they include Hodgkins and non-Hodgkins lym- The development from a normal cell to a cancerous cell is phomas Leukemias tend to proliferate as single cells and are ally a multistep process of clonal evolution driven by a detected by increased cell numbers in the blood or lymph. series of somatic mutations that progressively convert the cell Leukemia can develop in lymphoid or myeloid lineages from normal growth to a precancerous state and finally Historically, the leukemias were classified as acute or cancerous state hronic according to the clinical progression of the disease The presence of myriad chromosomal abnormalities in The acute leukemias appeared suddenly and progressed precancerous and cancerous cells lends support to the role of rapidly, whereas the chronic leukemias were much less ag. multiple mutations in the development of cancer. This has gressive and developed slowly as mild, barely symptomatic been demonstrated in human colon cancer, which progresses diseases. These clinical distinctions apply to untreated leuke- in a series of well-defined morphologic stages(Figure 22-4). mias; with current treatments, the acute leukemias often have lon cancer begins as small, benign tumors called adeno- a good prognosis, and permanent remission can often be mas in the colorectal epithelium. These precancerous tumors achieved. Now the major distinction between acute and grow, gradually becoming increasingly disorganized in their chronic leukemias is the maturity of the cell involved. Acute intracellular organization until they acquire the malignant leukemias tend to arise in less mature cells, whereas chronic phenotype. These well-defined morphologic stages of colon leukemias arise in mature cells. The acute leukemias include cancer have been correlated with a sequence of gene changes acute lymphocytic leukemia (ALL) and acute my involving inactivation or loss of three tumor-suppressor genes leukemia(AML); these diseases can develop at (APC, DCC, and p53) and activation of one cellular prolifer- have a rapid onset. The chronic leukemia ation oncogene(K-ras lymphocytic leukemia(CLL) and chronic myelogenous Studies with transgenic mice also support the role of multi- leukemia( CML); these diseases develop slowly and are seen in ple steps in the induction of cancer. Transgenic mice express- adults. ing high levels of Bcl-2 develop a population of small resting A number of B-and T-cell leukemias and lymphomas in B cells, derived from secondary lymphoid follicles, that have volve a proto-oncogene that has been translocated into the greatly extended life spans. Gradually these transgenic mice immunoglobulin genes or T-cell receptor genes. One of the develop lymphomas. Analysis of lymphomas from these mice best characterized is the translocation of c-myc in Burkitt has shown that approximately half have a c-myc translocation lymphoma and in mouse plasmacytomas. In 75% of Burkitt's to the immunoglobulin H-chain locus. The synergism of Myc lymphoma patients, c-myc is translocated from chromosome 8 and Bcl-2 is highlighted in double-transgenic mice produced to the Ig heavy-chain gene cluster on chromosome 14(see Chromosomal 7p eration Loss hypomethylation alterations epithelium epithelium FIGURE 22-4 Model of sequential genetic alterations leading to quence of genetic alterations. Adapted from B. Vogelstein and K. W. metastatic colon cancer. Each of the stages indicated at the bottom is Kinzler, 1993, Trends Genet. 9: 138 morphologically distinct, allowing researchers to determine the se.receptors. Expression of the receptor for epidermal growth factor, which is encoded by c-erbB, has been shown to be amplified in many cancer cells. And in breast cancer, increased synthesis of the growth-factor receptor encoded by c-neu has been linked with a poor prognosis. The Induction of Cancer Is a Multistep Process The development from a normal cell to a cancerous cell is usually a multistep process of clonal evolution driven by a series of somatic mutations that progressively convert the cell from normal growth to a precancerous state and finally a cancerous state. The presence of myriad chromosomal abnormalities in precancerous and cancerous cells lends support to the role of multiple mutations in the development of cancer. This has been demonstrated in human colon cancer, which progresses in a series of well-defined morphologic stages (Figure 22-4). Colon cancer begins as small, benign tumors called adeno￾mas in the colorectal epithelium. These precancerous tumors grow, gradually becoming increasingly disorganized in their intracellular organization until they acquire the malignant phenotype. These well-defined morphologic stages of colon cancer have been correlated with a sequence of gene changes involving inactivation or loss of three tumor-suppressor genes (APC, DCC, and p53) and activation of one cellular prolifer￾ation oncogene (K-ras). Studies with transgenic mice also support the role of multi￾ple steps in the induction of cancer. Transgenic mice express￾ing high levels of Bcl-2 develop a population of small resting B cells, derived from secondary lymphoid follicles, that have greatly extended life spans. Gradually these transgenic mice develop lymphomas. Analysis of lymphomas from these mice has shown that approximately half have a c-myc translocation to the immunoglobulin H-chain locus. The synergism of Myc and Bcl-2 is highlighted in double-transgenic mice produced by mating the bcl-2+ transgenic mice with myc+ transgenic mice. These mice develop leukemia very rapidly. Tumors of the Immune System Tumors of the immune system are classified as lymphomas or leukemias. Lymphomas proliferate as solid tumors within a lymphoid tissue such as the bone marrow, lymph nodes, or thymus; they include Hodgkin’s and non-Hodgkin’s lym￾phomas. Leukemias tend to proliferate as single cells and are detected by increased cell numbers in the blood or lymph. Leukemia can develop in lymphoid or myeloid lineages. Historically, the leukemias were classified as acute or chronic according to the clinical progression of the disease. The acute leukemias appeared suddenly and progressed rapidly, whereas the chronic leukemias were much less ag￾gressive and developed slowly as mild, barely symptomatic diseases. These clinical distinctions apply to untreated leuke￾mias; with current treatments, the acute leukemias often have a good prognosis, and permanent remission can often be achieved. Now the major distinction between acute and chronic leukemias is the maturity of the cell involved. Acute leukemias tend to arise in less mature cells, whereas chronic leukemias arise in mature cells. The acute leukemias include acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML); these diseases can develop at any age and have a rapid onset. The chronic leukemias include chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML); these diseases develop slowly and are seen in adults. A number of B- and T-cell leukemias and lymphomas in￾volve a proto-oncogene that has been translocated into the immunoglobulin genes or T-cell receptor genes. One of the best characterized is the translocation of c-myc in Burkitt’s lymphoma and in mouse plasmacytomas. In 75% of Burkitt’s lymphoma patients, c-myc is translocated from chromosome 8 to the Ig heavy-chain gene cluster on chromosome 14 (see 506 PART IV The Immune System in Health and Disease Chromosomal site Alteration Gene 5q Loss APC 18q Loss DCC 12p Activation K-ras 17p Loss p53 DNA hypomethylation Other alterations Normal epithelium Hyperproliferative epithelium Early adenoma Intermediate adenoma Late adenoma Carcinoma Metastasis FIGURE 22-4 Model of sequential genetic alterations leading to metastatic colon cancer. Each of the stages indicated at the bottom is morphologically distinct, allowing researchers to determine the se￾quence of genetic alterations. [Adapted from B. Vogelstein and K. W. Kinzler, 1993, Trends Genet. 9:138.]