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Prior to the discovery of the Philadelphia chromosome, no specific pattern of chromosomal ab- normalities in neoplasia had been observed. This is the likely reason that Boveri’s initial pro- posal was generally disregarded. However, following Rowley’s observation of the translocation resulting  in the formation  of the Philadelphia  chromosome  in CML, investigators  employed newer techniques  to determine whether any karyotypic  changes were specific to one or more histogenetic types of neoplasms.

Figure 6.6 portrays the chromosomes of the human karyotype, indicating positions of cer- tain proto- and cellular oncogenes and tumor suppressor genes as well as sites of translocations, deletions, trisomies, and inversions. The banding pattern seen is that of a single chromatid of each of the chromosomes from the human karyotype. All of the chromosomes, including those which as yet have not been involved in the genesis of any specific histogenetic neoplasm, are represented in the figure. As noted in the figure, most of the neoplasms associated with translo- cations, inversions, or deletions are leukemias. The reason for this is technical, in that examina- tion of the karyotypes  of leukemic  cells  is much  easier  than of the karyotypes  of solid neoplasms. However, the figure also shows chromosomal  alterations characteristically  seen in several sarcomas as well as epithelial neoplasms.  In most of the examples, the percentage  of patients exhibiting the specific chromosomal abnormality is less than 50%. However, in a num- ber of neoplasms the chromosomal abnormality is characteristically  greater than 50%, as noted in Table 6.7.

Since it is the leukemias and lymphomas that have revealed the most consistent and easily studied chromosomal aberrations, detailed investigations of a number of chromosomal translo- cations analogous to the Ph1 chromosome have been carried out and in turn have served as mod- els for similar chromosomal  aberrations  in neoplasms  of diverse types (Figure 6.6 and Table

6.7). Here three examples of structural aberrations  occurring in a high percentage  in specific neoplasms are considered in more detail.

The 8:14 Translocation in Burkitt Lymphoma

Burkitt lymphoma is endemic in certain parts of the continent of Africa (Chapter 11). A variant form of this disease is seen in the North American continent and other parts of the world. As noted from Table 6.7, an extremely high proportion  of individuals  with this disease exhibit a specific chromosomal  translocation.  A diagram of the translocation  is seen in Figure 6.7; the translocation  involves a disruption  of two genes involved in the breakpoint.  These are c-myc

Figure 6.6 Human chromosome  map showing position of oncogenes  (< lowercase),  translocation  and breakage sites (arrow with number in parentheses designating other chromosome involved in the transloca- tion), deletions (boxes with diagonal lines), trisomies (+), inversions (two-way arrows), and the notation of the specific neoplasm associated with the designated chromosomal abnormality (uppercase or combination of upper- and lowercase  letters). The karyotype  represents  Giemsa bands at the 400 band stage. The no- menclature for the cellular oncogenes is identical with that in Table 4.4, Chapter 4. The key to the abbrevi- ations of the neoplastic conditions designated in the figure is as follows, in alphabetical order: ALL, acute lymphocytic leukemia with t(4;11); AML, acute myelogenous leukemia with t(8;21); AMoL, acute mono- cytic leukemia with t(9;11); AMMoLe, acute myelomonocytic  leukemia with inversion of chromosome 16 (double reversed arrows); ANLL, acute nonlymphocytic  leukemia with deletion in chromosome  5; APL, acute promyelocytic leukemia with t(15;17); AW, aniridia “Wilms” tumor syndrome with small deletion of short arm of chromosome  11; BL, Burkitt’s lymphoma  and B-cell lymphoma  with t(8;14); CLL, chronic lymphocytic leukemia with t(11;14) and trisomy of chromosome 12; CML, chronic myelogenous leukemia with t(9;22); Endca, endometrial carcinoma with deletion of the X chromosome; EW, Ewing sarcoma with t(11;22)(q24;q12);  FL, follicular lymphoma  with t(14;18); MLS, myxoid liposarcoma  t(12;16)(q13;p11); Mng, meningioma with deletion of chromosome 22; MPT, mixed parotid gland tumor with t(3;8); Nb, neu- roblastoma with deletion of portion of long arm of chromosome 1; OPA, ovarian papillary adenocarcinoma with t(6;14); Rb, retinoblastoma  with deletion of segment of short arm of chromosome 13; RCC, renal cell carcinoma with t(3;8); SCLC, small-cell lung cancer with deletion of short arm of chromosome 3; SS, syn- ovial sarcoma t(X:18)(p11;q11).  For further details of this map, the reader is referred to the text and the review by Yunis (1983) as well as Rowley (1990) and Mitelman and Heim (1990).

present on chromosome 8 and the heavy chain of the immunoglobulin gene family (Chapter 15). The figure indicates  two different  genes resulting  from the translocation,  one seen predomi- nantly in African Burkitt lymphoma and the other seen more commonly in North American Bur- kitt lymphoma  (Haluska  et al., 1987).  Other  variants  have  also been  reported  involving chromosome 8 with translocations  to chromosome 2 or chromosome 22 (Aisenberg, 1984). In many B-cell lymphomas with translocations that involve immunoglobulin genes (Chapter 16), a significant rearrangement of the immunoglobulin genes may be found in the lymphoma cell ge- nomes (Cleary et al., 1984; Haluska et al., 1986). Because of the nature of the normal somatic recombination  seen in immunoglobulin  genes (Chapter 16), it is possible that the formation of the translocation may be related to this normal process seen in B cells. A similar finding of the relationship of chromosomal abnormalities to the T-cell receptor genes (Chapter 19) has led to similar proposals of the mechanisms of chromosomal abnormalities in T-cell neoplasms (Boehm and Rabbitts, 1989).

Despite  extensive  knowledge  of the detailed  structure  of the fusion of the c-myc and immunoglobulin genes at the breakpoint, the molecular mechanism of the dysregulation of the c-myc proto-oncogene that occurs in this condition remains unclear (Aisenberg, 1993). As seen in Figure 6.7, the sites of disruption  of the two genes involved  may differ slightly between different neoplasms, especially in different parts of the world. Croce and Nowell (1985) sug- gested that enhancer elements within the immunoglobulin gene that had been translocated may serve to increase transcription  of the c-myc proto-oncogene,  but as yet this concept remains theoretical.

Figure 6.7 Differences  in the t(8:14)  chromosome  translocation  of the African  Burkitt  lymphoma (P3HR-1)  and sporadic  Burkitt  lymphoma  (CA 46) with only the 14q+ chromosome  illustrated  in each case. In the case of African Burkitt lymphoma, the breakpoint lies upstream of the joining (J5) region of the heavy immunoglobulin  chain on chromosome  14 and more than 50 kb 5′ of the intact c-myc on chromo- some 8. In contrast, in sporadic Burkitt lymphoma, this example demonstrates a breakpoint much farther 3′ into the immunoglobulin  heavy chain gene region and the elimination  of the first exon of c-myc. (From Haluska et al., 1987, with permission of the authors and publisher.)

The 14:18 Translocation in Follicular Lymphomas

In general, it has been stated that translocation  between chromosomes  14 and 18 is the most common cytogenetic abnormality observed in malignant lymphomas (Rowley, 1988). As noted in Table 6.7, as many as 90% of follicular lymphomas may exhibit this abnormality. The translo- cation places the IgM heavy chain gene on chromosome 14 in juxtaposition to the bcl-2 cellular oncogene on chromosome  18 (Figure 6.8). The bcl-2 gene, designation  for B-cell lymphoma/ leukemia, has been shown to play an important role in apoptosis, programmed  cell death (cf. Bagg and Cossman, 1993). The bcl-2 gene product appears to inhibit the process of apoptosis in both normal and neoplastic cells. In the translocation, the coding region of the bcl-2 gene is left intact, and there is a marked deregulation of the gene following translocation. This in turn leads to an inhibition of programmed cell death of B lymphocytes with continued expansion and po- tential for other secondary genetic events that are seen in lymphomas.

The 15:17 Translocation in Acute Promyelocytic Leukemia

Acute promyelocytic leukemia is a distinct subtype of acute nonlymphocytic leukemias in which a translocation occurs between chromosomes 15 and 17 with the breakpoints noted in Table 6.7. Larson et al. (1984) have argued that every patient with this condition exhibits the 15:17 translo- cation. A more detailed scheme of the translocation  may be seen in Figure 6.9. As noted, the genes involved are the retinoic acid receptor-α  (RAR-α)  and a gene termed PML (abbreviation for promyelocytic leukemia). The gene resulting from the translocation involves the amino ter- minal two-thirds of the coding region of the PML gene. A large portion but not all of the RAR-a receptor comprises the other portion of the fused gene (de Thé et al., 1991). While there have been several suggested mechanisms by which the fused gene product interferes with the normal function of the receptor that plays a role in promyelocytic differentiation, the important clinical characteristic of this disease is that more than 85% of patients respond to the administration of retinoids by an induced differentiation in vivo of the leukemic cells, resulting in a remission of the disease.

Figure 6.9 Diagram  of the genesis and dimerization  of the PML/RAR-α fusion protein. At the upper part of the figure the reciprocal translocations  between the long arms of chromosomes  15 and 17 in APL are shown with the derived  (der) chromosomes  in the center. In the middle of the figure are shown the protein sequences  for the PML and RAR-α  genes with the upper single arrowheads  associated  with the dashed line indicating the most common breakpoints involved in the translocations  in APL. At the bottom of the figure are shown possible mechanisms  by which the fusion of the two genes may lead to leukemo- genesis,  including  heterodimerization with wild-type  PML and inactivation  of the latter, inactivation  of other retinoid receptors (RXR), and inactivation of these as well as homodimerization  of the fusion proteins with subsequent binding to PML and/or RAR-α  target genes. (From Warrell et al., 1993, with permission of the authors and publisher.)

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