Chromosome Translocations and Human Cancer1

[CANCER RESEARCH 46, 6019-6023, December 1986]

Perspectives in Cancer Research Chromosome Translocations and Human Cancer1

Carlo M. Croce2

The Wistar Institute, Philadelphia, Pennsylvania 19104

The cytogenetic analysis of human cancer cells by standard rearrangement, somatic cell hybrids between mouse myeloma and by high resolution banding techniques indicates that more cells and Burkitt's lymphoma cells with the t(8; 14) chromosome than 90% of human malignancies carry clonal cytogenetic translocation were produced and analyzed with probes specific changes (1). The discovery of the Philadelphia chromosome in for the genes for the variable and constant regions of the human the neoplastic cells of patients with CML3 (2) and the subse heavy chains (13). The results of this analysis indicated that the quent findings that the great majority of human hematopoietic human heavy chain locus is split at various sites by the chro malignancies carry specific chromosomal alterations (3, 4) have mosomal translocation and that the genes for the variable suggested that such nonrandom chromosomal changes may be regions translocate to the involved chromosome 8 (8q-), while involved in the pathogenesis of human malignancies. This view, the genes for the constant regions remain on the involved however, was not shared by many investigators outside the field chromosome 14 (14q+) (13). Analysis of the hybrids for the of cancer cytogenetics, who regarded such chromosomal alter expression of human heavy chains also indicated that the ex ations as epiphenomena of the neoplastic process. pressed human heavy chain locus in Burkitt's lymphoma resides Recent developments in the analyses of genes involved in the on the normal chromosome 14 (13). Thus the chromosomal chromosomal rearrangements observed in human leukemias translocation directly involves the unexpressed heavy chain and lymphomas indicate that such rearrangements are the locus. Since the genes for the variable regions (VH) translocate critical steps involved in the pathogenesis of most human to the 8q- chromosome, while the constant region genes (CH) leukemias and lymphomas and that they may also play an remain on chromosome 14, it was also clear that the VH genes important role in the pathogenesis of human solid tumors. were more distal than the CH genes at band q32 of chromosome 14 (13). In hybrids between mouse myeloma cells and Burkitt's The Lesson Learned from the Genetic Analysis of Burkitt's lymphoma cells with the variant t(8;22) (q24;qll) and the Lymphoma t(2;8)(pll;q24) chromosome translocations it was shown that the loci for the immunoglobulin light chains were also split by Perhaps the most striking example of correlation between the translocations. Since the VK and VX genes remain on the specific chromosomal translocations and malignancy is the case involved chromosomes 2 (2p~) and 22 (22q~), respectively, of Burkitt's lymphoma, an extremely aggressive B-cell neo while either the CKor the CX genes translocate to the involved plasm predominantly affecting children. In this malignancy, chromosome 8, it was concluded that the genes for VÂ«and VX Manolov and Manolova detected a marker chromosome 14 were more proximal than the constant region genes on chro (14q+) that was longer than the normal chromosome 14 (5). mosomes 2 and 22, respectively (14, 15). In the variant cases Subsequently, Zech et al. (6) found that the 14q+ chromosome of Burkitt's lymphoma, the expressed X or K light chain gene resulted from a translocation of a small segment of the distal also resides on the normal chromosome 22 or 2, respectively region of chromosome 8 to the distal end of chromosome 14. (14,15), while the unproductively rearranged Xor Klocus resides Subsequently, other investigators in America, Europe, and Ja on the translocation chromosome (14, 15). pan detected variant chromosome translocations in a minority The human homologue, c-myc, of the \-myc oncogene present of human Burkitt's lymphomas (7, 8). In those cases, the same in avian myelocytomatosis virus resides on chromosome 8 at segment of chromosome 8 translocates to either chromosome band q24 and is translocated to the heavy chain locus on the 22 or 2. In approximately 75% of Burkitt's lymphomas, the 14q+ chromosome in Burkitt's lymphomas with the t(8;14) distal end of the long arm of chromosome 8 (q24-qter) trans chromosome translocation (16). Thus the human c-myc onco locates to the long arm of chromosome 14 at band q32 [a gene was thought to play a critical role in the pathogenesis of t(8;14)(q24;q32) chromosomal translocation]; 16% carry a this malignancy (16, 17). Analysis of Burkitt's lymphoma cells t(8;22)(q24;ql 1) chromosome translocation, and only 9% carry with the t(8; 14) chromosome translocations for rearrangements a t(2;8)(pl I;q24) chromosome translocation. of the c-myc oncogene indicated that the translocated oncogene Because the distal end of chromosome 8 is involved in trans- may be rearranged at its 5' end, so that the 5' end of the location with chromosome 14, 22, or 2, each of which carries a oncogene is more proximal than its 3' end at band 8q24 (16- locus for human immunoglobulins (9-12), it was speculated 18). Molecular analysis of the c-myc oncogene indicated that it that the human immunoglobulin genes might play an important role in the chromosome rearrangements observed in Burkitt's is formed by three exons separated by two introns (19). Since the first exon contains termination codons on all three reading lymphomas and in the pathogenesis of this disease (10). To frames, it is noncoding (19). The first ATG signal for initiation determine whether the heavy chain locus, which resides on of protein synthesis is at the beginning of the second exon and chromosome 14 (9), is directly involved in the chromosomal is followed by an open reading frame encoding for a protein of Received 5/2/86; revised 6/5/86; accepted 6/16/86. 439 amino acids and a molecular weight of 48,812 (19). The c- 1This study was supported in part by a grant from the NIH, National Cancer Institute (CA39860). myc oncogene has two promoters separated by approximately 2To whom requests for reprints should be addressed, at The Wistar Institute, 160 nucleotides, and its transcripts originate at two initiation 3601 Spruce Street, Philadelphia, PA 19104. sites (20). When the c-myc gene is decapitated of its first exon 3The abbreviations used are: CML, chronic myelogenous leukemia; ALL, acute lymphocytic leukemia; CLL, chronic lymphocytie leukemia; HTLV-1. because of breakpoints within the first c-myc intron, new cryptic human T-cell leukemia virus I; ber, breakpoint cluster region. promoters are activated within the first c-myc intron, and 6019 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1986 American Association for Cancer Research. CHROMOSOME TRANSLOCATIONS AND HUMAN CANCER abnormal transcripts initiate from different cryptic transcrip Burkitt's lymphoma cells for the expression of the translocated tion sites (21). In these novel transcripts, the first AUG codon c-myc oncogene versus expression of that on normal chromo for initiation of protein synthesis is the same as that in the some 8 also indicated that the gene on the normal chromosome normal c-myc transcript. Thus the c-myc product in Burkitt's 8 is either transcriptionally silent or expressed at extremely low lymphomas with or without c-myc gene rearrangement is iden levels, while the translocated gene is transcribed constitutively tical to the normal c-myc gene product. at elevated levels (21). Thus, the consequence of the three It appears that most African Burkitt's lymphomas (Burkitt's different chromosomal translocations is a deregulation of the lymphoma is endemic in equatorial Africa) express only cyto- transcription of the c-myc gene involved in the chromosomal plasmic or membrane-bound immunoglobulin, whereas spo translocation (15, 16, 26). radic Burkitt's lymphomas secrete human immunoglobulins. It has been postulated that the deregulation of the c-myc gene Thus, endemic and sporadic Burkitt's lymphomas might involve is due to alteration of the first exon of the c-myc gene or to its cells at different stages of B-cell differentiation (22). Interest decapitation (18). However, in several Burkitt's lymphomas, ingly, the great majority of African Burkitt's lymphomas are the c-myc oncogene involved in the translocation is perfectly characterized by rearrangement of the heavy chain locus in the normal, and an altered or decapitated c-myc oncogene derived JH region or 5' to it, whereas the sporadic Burkitt's lymphoma from Burkitt's lymphoma is not expressed in B-cells unless it might have the rearrangement in a heavy chain switch region, is juxtaposed to an immunoglobulin locus or to an immuno Sji, ST, or SÂ«(22). These switch regions are normally involved globulin enhancer (26-28). It seems likely that alterations in in heavy chain isotype switching. In most of the African Burk the structure of the c-myc oncogene in Burkitt's lymphoma are itt's lymphomas, the break on chromosome 8 is 5' to the c-myc secondary and may occur during tumor progression. oncogene, very often more than 30 kilobases 5' to the translo Analysis of somatic cell hybrids between Burkitt's lymphoma cated c-myc gene ( 17). By contrast, in sporadic Burkitt's lym cells and cells of different lineages also indicates that the phoma, rearrangements often involve the first intron of the c- expression of the activated c-myc oncogene involved in the myc oncogene (17, 23). translocation is B-cell specific (26, 27). This finding is consis We have used somatic cell genetic techniques to show that tent with the interpretation that tissue-specific enhancing ele different heavy chain enhancing elements are involved in c-myc ments within the immunoglobulin genes are responsible for c- activation (24, 25). The enhancer between JH and Sfi is involved myc deregulation. in c-myc oncogene activation in these cases where the rearrange ments occur within Jfl or 5' to the JH segment (24, 25). We Cloning of Genes Involved in B-Cell Neoplasia have postulated the existence of other enhancing elements within the heavy chain locus which are 3' to the involved switch Since many human B-cell neoplasms carry translocations regions and which seem to activate gene transcription only in involving region 14q32, where the heavy chain locus resides more differentiated B-cells (24, 25). Thus at least two different (29), and since the c-myc oncogene in Burkitt's lymphoma is types of enhancers seem to be present within the heavy chain deregulated because of its proximity to the heavy chain locus locus. One is located in the region between S^ and C/u (23, 24). (26), we reasoned that it should be possible to isolate human This enhancer is "promiscuous" and can activate gene transcrip genes involved in the pathogenesis of human B-cell neoplasms tion in B-cells at different stages of B-cell differentiation, from by taking advantage of their proximity to the heavy chain locus. pre-B to plasma cells (24-26). The second enhancer may be 3' Therefore we hybridized mouse plasmacytoma cells with human to the CÂ«2gene and may activate gene transcription in termi leukemic cells derived from a patient with CLL of the B-cell nally differentiated or nearly terminally differentiated B-cells type carrying a t(ll;14) (ql3;q32) chromosome translocation (24-26). Interestingly, both types of enhancers may activate (29). Such a translocation is observed in CLL (30), in diffuse gene transcription over considerable chromosomal distances B-cell lymphomas (3), and in multiple myeloma (31). Analysis (possibly over 100 kilobases of DNA) (24-26). of the hybrid cells indicated that the heavy chain locus was split Analysis of the transcription of the c-myc oncogene involved by the chromosome translocation (29). We then prepared a in the chromosome translocation versus that of the normal c- DNA library from this case of CLL, cloned the breakpoint myc gene on the normal chromosome, using somatic cell hy between chromosomes 11 and 14, and identified a locus we brids between mouse myeloma cells and Burkitt's lymphoma termed bcl-\ (B-cell lymphoma/leukemia 1), which is involved cells carrying each of the three different chromosomal translo in the t(l 1;14) chromosome translocation (32, 33). cations (15, 16, 26), revealed that, while the normal c-myc Using a similar procedure, we cloned the chromosome break oncogene on normal chromosome 8 is transcriptionally silent, points involved in the t(14;18) (q32;q21) chromosome translo the c-myc gene involved in each one of the three different cation (34) observed in the most common human hematopoietic chromosomal translocations is transcribed constitutively at el malignancy, follicular lymphoma (35). Chromosome 18-spe- evated levels. Thus, the juxtaposition of the c-myc oncogene to cific probes flanking the breakpoints were then used to detect each of the three immunoglobulin loci leads to the transcrip- DNA rearrangements in most human follicular lymphomas (34, tional deregulation of c-myc (15, 16, 26). Similar analysis with 35) and to detect transcripts of a gene we called bcl-2, which is hybrids of other hematopoietic cells, including human lym- involved in the pathogenesis of this human malignancy (35). phoblastoid cells expressing the normal c-myc oncogene on Interestingly, most of the breakpoints involve the 3' end of the chromosome 8, showed that the normal c-myc oncogene is bcl-2 gene or regions distal to it on chromosome 18 and involve repressed in a plasma cell background (26). These results are one of the JH segments of the heavy chain locus on chromosome consistent with the interpretation that, while the c-myc onco 14 (36). Thus the enhancer located between JH and S is always gene on normal chromosome 8 responds to normal transcrip- juxtaposed to the involved bcl-2 gene, leading to its deregulation tional control, the c-myc oncogene involved in the reciprocal (34-36). Analysis of the structure of the bcl-2 gene revealed chromosomal translocations observed in Burkitt's lymphomas that it is formed by two exons separated by an intron of at least does not and is expressed constitutively at elevated levels in 60 kilobases in length. Thus the heavy chain enhancer is at terminally differentiated B-cells (15, 16, 26). Direct analysis of least 65-70 kilobases 3' of the promoters of the bcl-2 gene (36), 6020 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1986 American Association for Cancer Research. CHROMOSOME TRANSLOCATIONS AND HUMAN CANCER suggesting that the enhancers within the heavy chain locus The Locus for the a-Chain of the T-Cell Receptor Is Involved in activate transcription over considerable chromosome distances the Specific Rearrangements Observed in T-Cell Neoplasms and (>60 kilobases) (36). Deregulates Protooncogene Transcription These findings indicate that one can take advantage of spe The locus for the Â«-chainof the T-cell receptor maps at band cific chromosome rearrangements to isolate genes involved in human B-cell neoplasms. The study of the structure, organiza 14qll (39), a chromosomal region also involved in rearrange tion, and function of these genes may provide insight into the ments (predominantly translocations and inversions) in most mechanisms of control of B-cell proliferation and into the T-cell neoplasms (40, 41). This finding suggested that the Â«- genetic mechanisms involved in the development of B-cell neo locus of the T-cell receptor might play a critical role in T-cell plasms. leukemias and lymphomas similar to that of the immunoglob ulin genes in B-cell malignancies (39). Analysis of hybrids between mouse leukemic T-cells and human leukemic cells from The Chromosome Translocations Observed in B-Cell Neoplasms patients with T-cell ALL carrying a t(ll;14)(pl3;ql 1) chro Are Catalyzed by the Same Enzymes Involved in Immunoglobulin mosome translocation (42) indicates that the T-cell receptor a- Gene Rearrangement locus is split by the translocation, that the breakpoints occur between the T-cell receptor Va and Ca genes, and that the VÂ« DNA sequence analysis of the breakpoints involved in the genes are proximal to the Ca gene at band 14qll (42). Thus t(ll;14) and in t(14;18) chromosome translocations indicated that these translocations involve the 5' end of one of the JH the locus for the a-chain of the T-cell receptor is directly involved in the chromosome rearrangements observed in most segments of the heavy chain locus (33, 37). This region of the human T-cell neoplasms (42). JH segments participates in the D-J rearrangements observed Recently we observed two cases of T-cell leukemias carrying during physiological V-D-J heavy chain joining. Stretches of a t(8;14) (q24;qll) chromosome translocation (43). In these extranucleotides were also found at joining sites (33, 37), an two leukemias, the breakpoints on chromosome 8 occurred 3' observation of considerable interest in light of the report of Alt to the involved c-myc oncogene, and the breakpoint on chro and Baltimore of extranucleotides (N regions) at joining sites mosome 14 occurred in joining segments (43). Thus the rear in rearranged immunoglobulin genes (38). These extranucleo rangements observed in these T-cell leukemias parallel those tides are presumably added at joining sites by the enzyme observed in variant Burkitt's lymphomas (14, 15). We also terminal transferase during the pre-B stage of cell differentia examined the expression of the c-myc locus involved in the tion (38). Thus it appeared that the t(ll;14) and the t(14;18) chromosome translocations occur during the process of V-D-J translocation versus that on the normal chromosome 8 in hy brids with mouse leukemic T-cells (43). Interestingly, the hy joining (33, 37). Since the putative V-D-J joining enzyme brids expressed only the c-myc gene involved in the transloca requires the presence of signal sequences, i.e., heptamers and tion, while the c-myc gene on normal chromosome 8 was nonamers separated by a spacer of 12 nucleotides on one side completely silent (43). We concluded that the translocation of and of 23 nucleotides on the other side, it was of interest to the locus for the a-chain of the T-cell receptor to a cellular determine whether such signal sequences were present on chro protooncogene leads to its transcriptional deregulation (43). mosomes 11 and 18 near breakpoints. Since the spacer between heptamer and nonamer at the 3' end of the involved JH segment This observation suggests that the a-locus of the T-cell recep tor contains genetic elements capable of activating gene tran is 23 nucleotides in length, the spacer on these 2 chromosomes scription in cis over considerable chromosomal distances. Thus should be 12 nucleotides in length. Indeed, analysis of the DNA it should be possible to isolate most of the human genes involved sequences of normal chromosomes 11 and 18 in proximity of in T-cell leukemias and lymphomas by taking advantage of the chromosome breakpoints indicated the presence of signal specific chromosomal rearrangements involving band 14qll sequences for joining with a spacer of 12 nucleotides (33, 37). and by using "chromosome walking" techniques (33, 35). This Thus the chromosomal translocations observed in B-cell neo plasms with the t(ll;14) and the t(14;18) chromosome trans- approach should enable identification of most of the genes that are directly and primarily involved in the pathogenesis of hu locations are catalyzed by the same enzyme that is involved in man B- and T-cell neoplasms. V-D-J joining (33, 37). Presumably the V-D-J joining enzyme mistakenly joins two separated segments of DNA on two dif ferent chromosomes instead of on the same chromosome, lead Presence of Two Specific Chromosome Translocations in Human ing to chromosome translocation. Sequences similar to the Leukemias signal sequences for joining may be present at many different sites in the human genome. Most likely, the translocations are Some human pre-B-cell leukemias have been reported that selected for because of their ability to lead to neoplastic trans carry a t(8;14) and a t(14;18) chromosome translocation in the formation. Similar translocations involving many different sites same cells (44). We thought it unlikely that these two translo may go unrecognized because they do not result in malignant cations, hallmarks of Burkitt's lymphoma and follicular lym- transformation. On the contrary those translocations that result phoma, respectively, occurred at the same time in the same in the juxtaposition of a cellular protooncogene to immuno cells (44). Since the phenotype of B-cell neoplasms with a globulin heavy chain enhancing elements lead to B-cell neopla t(14;18) chromosome translocation is that of a low-grade ma sia. Thus the chromosomal translocations observed in B-cell lignancy, while the phenotype of B-cell neoplasms with the tumors provide cancer researchers with the tools to identify and t(8;14) chromosome translocation is that of a high-grade malig characterize the genes that are directly involved in B-cell neo nancy, we speculated that the t(14;18) chromosome transloca plasia (22). tion precedes the t(8;14) chromosome translocation (3, 44). While the molecular basis of the chromosomal translocations The t(14;18) translocation probably occurred during V-D-J involving switch regions is not yet clear, it seems likely that joining and led to the expansion of a clone of low-grade malig they occur during the process of immunoglobulin heavy chain nancy. This, in turn, resulted in an increased probability of an switching. additional chromosome translocation during immunoglobulin 6021 Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1986 American Association for Cancer Research. CHROMOSOME TRANSLOCATIONS AND HUMAN CANCER

gene rearrangement (35, 36). The t(8;14) translocation then led control, leading to malignancy. In CML cells the mechanisms to a very aggressive B-cell malignancy (44). The same scenario of malignant transformation seem to involve the expression of might occur in Burkitf s lymphoma. In equatorial Africa, where an altered gene product that acquires protein kinase activity. Burkitt's lymphoma is endemic, children are infected by Ep- The expression of this altered gene product is associated with stein-Barr virus and malaria. This could result in a polyclonal a low grade malignancy (CML). The blastic crisis that is ob expansion of virus-infected cells rearranging their immunoglob- served in CML patients may then be due to additional genetic ulin gene. This, in turn, would increase considerably the prob changes. Additional and consistent chromosomal alterations ability that a chromosome translocation will occur during im- have in fact been detected in CML cases in blastic crisis. munoglobulin gene rearrangement. In the case of most solid tumors, unfortunately, cytogenetic Similarly, leukemias of patients in the region of Japan where analysis has not yet provided the molecular geneticists with the HTLV-1 is endemic have the same chromosome translocations information necessary to identify the critical genes involved in and inversions that are observed in T-cell leukemias and lym- the malignant process. The molecular mechanisms in the ma phomas observed in Europe and America in the absence of lignant transformation of cells of solid tumors might involve HTLV-1 (45). Thus HTLV-1 may just be expanding the pool multiple steps, since these cells must escape several levels of of proliferating T-cells rearranging T-cell receptor genes and different environmental controls and restrictions. Thus, it may then increasing the probability of a chromosome translocation be difficult to find common cytogenetic differences in such and consequent T-cell neoplasia (42, 43). tumor cells. However, quite likely, such nonrandom chromo somal alterations will be found, at least in some of the solid tumors, and will provide the basis for a rational molecular The Lesson Learned from the Analysis of Chronic Myelogenous genetic approach to the pathogenesis of human solid tumors. Leukemia

In most CMLs, a translocation between chromosomes 9 and References 22, t(9;22)(q24;ql 1), has been identified (4). This translocation results in the formation of a small marker chromosome, named 1. Yunis, J. J., Oken. M. M.. Kaplan, M. E., Ensrud, K. M., Howe, R. R., and Theologides, A. Distinctive chromosomal abnormalities in histologie sub Philadelphia chromosome (2). In this translocation, the human types of non-Hodgkin's lymphoma. N. Engl. J. Med.. 307:1231-1236, 1982. homologue of the v-abl oncogene of Abelson leukemia virus, c- 2. Nowell, P. C., and Hungerford, D. A. A minute chromosome in chronic abl, is translocated from its normal position on chromosome 9, granulocytic leukemia. Science (Wash. DC), 132: 1497, I960. 3. Yunis, J. J. The chromosomal basis of human neoplasia. Science (Wash. band q34, to chromosome 22 at band qll (46). Molecular DC), 221: 227-236, 1983. analysis of the region of chromosome 22 involved in the rear 4. Rowley. J. D. Identification of the constant chromosome regions involved in rangements indicated that most breakpoints occur within a human hÃ©matologiemalignant disease. Science (Wash. DC), 216: 749-751, 1983. short segment (5.8 kilobases in length) of DNA called the ber 5. Manolov, G., and Manolova, Y. Marker band in one chromosome 14 from (46). Analysis of c-abl and ber transcripts in CML cells indi Burkitt lymphoma. Nature (Lond.), 237: 33-34, 1972. cated that these leukemic cells express an aberrant hybrid c- 6. Zech, L., Haglund, V., Nilson, N., and Klein, G. Characteristic chromosomal abnormalities in biopsies and lymphoid cell lines from patients with Burkitt abl-bcr RNA that is translated into an aberrant c-abl-bcr protein and non-Burkitt lymphomas. Int. J. Cancer, 17: 47-56, 1976. with a molecular weight of 210,000 with protein kinase activity 7. van den Berghe, H., Parloir, C., Gosseye, S., Eglebienne, V., Cornu, G., and Sokal, G. Variant translocations in Burkitt lymphoma. Cancer Genet. 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Carlo M. Croce

Cancer Res 1986;46:6019-6023.

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