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Chromosome translocations: dangerous liaisons revisited
Author: Janet Rowley
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"� 2001 Macmillan Magazines Ltd PERSPECTIVES that chromosome abnormalities were an effect and not a cause of cancer persisted until the early 1970s, when the application of chromosome banding (BOX 1) allowed indi- vidual chromosomes and regions of chromo- somes to be identified. This technique allowed cancer researchers to identify specific chromosome abnormalities that were often uniquely associated with human leukaemias, lymphomas and solid tumours. The Philadelphia story In 1959, Peter Nowell and David Hungerford identified the first chromosome abnormality that was consistently associated with a human malignant disease. The next year, they reported that cells from CML patients had a normal number of chromosomes, but that one chro- mosome was too small 3 . The consistent pres- ence of this marker chromosome in CML patients was quickly confirmed by other cancer researchers, and this marker became known as the Philadelphia or Ph 1 chromosome, now called just Ph. This small chromosome was thought to be caused by a simple deletion, and the loss of DNA from the chromosome was pro- posed to be the cause of the leukaemia ? an idea that was accepted for more than 10 years. The use of chromosome banding markedly changed this perception. In 1972, Rowley discovered that the Ph chromosome was not caused by a deletion, but by an inter- change between the end of the long arm of chromosome 9 and the long arm of chromo- some 22 (REF. 4). In this translocation, a large portion of chromosome 22 moved to chro- mosome 9, and it was assumed that a very small portion of chromosome 9 also moved to chromosome 22. As a consequence, the Ph chromosome was much smaller than the normal chromosome 22 (BOX 1). Chromosome 9. The next step, which was to clone the translocation breakpoints, occurred a decade later and began to reveal how these chromosomal rearrangements caused leukaemia. c-ABL, the human cellu- lar homologue of the transforming sequence of Abelson murine leukaemia virus (A-MuL V), was known to be located on chromosome 9. In 1982, Dutch researchers investigated whether c-ABL was affected by the CML-associated transloca- tion. They hybridized human and viral ABL probes to DNA blots of SOMATIC CELL HYBRIDS that contained only the Ph chromosome, and observed that the probe hybridized with the Ph chromosome, but not the 9q + derivative of the translocation 5 . From this, the authors concluded that in CML cells, 37. Pegram, M. D., Konecny, G. & Slamon, D. J. The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treat. Res. 103, 57?75 (2000). 38. Moore, M. A. The clinical use of colony stimulating factors. Annu. Rev. Immunol. 9, 159?191 (1991). 39. Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346?355 (1994). 40. Bhattacharjee, A. et al. Classification of human lung carcinomas by mRNA expression analysis. Proc. Natl Acad. Sci. (in the press). Acknowledgements This work was supported, in part, by grants from the National Heart, Lung and Blood Institute and by a grant from the National Cancer Institute. The authors appreciate the assistance of the staff of the Cancer Centres Programme of the National Cancer Institute, particularly J. Bhorjee. Valuable references were provided by G. Canellos and D. Livingston. We also thank T. Church for his efforts in manuscript preparation. Online links DATABASES The following terms in this article are linked online to: CancerNet: http://cancernet.nci.nih.gov/ breast cancer | colorectal cancer | prostate oncology LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/p53 Medscape DrugInfo: http://promini.medscape.com/drugdb/search.asp Glivec | Herceptin FURTHER INFORMATION NCI Cancer Centre Programme: http://www.nci.nih.gov/cancercenters/ The Nobel Prize in Physiology or Medicine 1990: http://www.nobel.se/medicine/laureates/1990/index.html Science, the Endless Frontier: http://www1.umn.edu/scitech/assign/vb/VBush1945.html Timeline of Vannevar Bush?s achievements: http://www.cs.brown.edu/research/graphics/html/info/ timeline.html The Warren G. Magnesen Clinical Center: http://www.cc.nih.gov/home.cgi Access to this interactive links box is free online. NATURE REVIEWS | CANCER VOLUME 1 | DECEMBER 2001 | 245 Chromosome translocations: dangerous liaisons revisited Janet D. Rowley TIMELINE Although it has been clear for more than a century that the chromosomes in human tumour cells are often wildly abnormal, there has been controversy as to whether these changes are primary events or are merely secondary epiphenomena that reflect the genomic instability of these cells. The prevailing view for most of this period was that chromosome changes were secondary events. What happened to change this view? Early observations that specific recurring chromosome aberrations, such as transloca- tions, were often associated with a particular type of leukaemia, lymphoma or sarcoma led researchers to believe that chromosome rearrangements might be involved in cellular transformation. Simultaneously, technical advances, such as recombinant DNA technol- ogy and the creation of DNA probes, allowed the identification of the genes that are affected by these chromosome rearrangements. The discovery that some of these genes were the human counterparts of viral oncogenes led to the realization that rearrangements were involved in transformation. In a sense, the findings of cytogeneticists and tumour virolo- gists validated each other ? the association between oncogenes and chromosome translo- cations supported a role for each in human cancer pathogenesis. The recent reports that STI-571 (Glivec), a drug that inhibits the BCR?ABL fusion protein as well as other kinases, is highly effective in treating chronic myelogenous leukaemia (CML) has captured the worldwide attention of physicians, scien- tists and the public. The fact that this success is the result of research that started more than 40 years ago is not widely appreciated. Early work on cancer cytogenetics In 1890, the German biologist David von Hansemann noticed that tumour cells with chromosome abnormalities also contained several spindle bodies and other mitotic aberrations (see TIMELINE). However, Theodor Boveri provided the most compre- hensive synthesis of the data and proposed that these abnormalities were the cause of malignant transformation 1 . Little was made of this observation until the 1950s, when sev- eral scientists ? including Sajiro Makino in Japan, Theodore Hauschka in the United States and Albert Levan in Sweden ? discov- ered that virtually all tumour cell lines had chromosomal aberrations, frequently con- taining over 100 chromosomes per cell, including DICENTRIC and RING CHROMOSOMES 2 . Cell lines from the same tumour type did not, however, have the same aberrations, so these abnormal karyotypes were assumed to be a result of the inherent genomic instability of cancer cells, rather than a cause. The view � 2001 Macmillan Magazines Ltd 246 | DECEMBER 2001 | VOLUME 1 www.nature.com/reviews/cancer PERSPECTIVES patients revealed that the t(9;22) created a fusion between the 5? part of BCR and the 3? part of ABL 8 . The portion of the human ABL gene that was contained in the fusion RNA encompassed the coding region, which is homologous to the mouse leukaemia-associ- ated v-Abl gene. Later studies showed that the t(9;22)/BCR?ABL fusion was essential for the development of CML 9 . Although the Ph chromosome was initial- ly only associated with CML, lymphocytes from patients with acute lymphoblastic leukaemia (ALL), especially adults, were found to have a similar translocation 10 .The ALL-associated BCR breakpoint is different, however, from the one associated with CML. In ALL, the translocation usually occurs in the first intron of BCR, resulting in a much small- er portion becoming fused to exon 2 of ABL 11 . The murine Abl gene was well studied and was known to be a tyrosine kinase 12 . In 1984, CML cells were shown to express an altered form of c-ABL with tyrosine kinase activity, indicating a mechanism of action for this oncogene 13 . This activity was greater in Ph- positive ALL cells than in CML cells, and cor- related with the fact that ALL is the more aggressive form of leukaemia. But, the reason why the inclusion of a smaller segment of BCR in the fusion protein would increase kinase activity is still unknown. Analysis of mice receiving bone marrow cells infected with a retrovirus that encodes BCR?ABL showed that this fusion protein was sufficient to cause a myeloproliferative syndrome closely resembling the chronic phase of CML 14 . This is not, however, the only genetic change associated with CML 15 , but the basic research that identified this cancer-caus- ing fusion protein as a tyrosine kinase that is Chromosome 22. In 1984, John Groffen and colleagues examined DNA samples from 19 CML patients for rearrangements on chro- mosome 22 using Ph translocation break- point probes 7 . They found that the Ph chro- mosome breaks usually occurred within a 5.8-kb region, which they named the ?break- point cluster region? (BCR) 7 . This eventually became the name of the chromosome 22 gene that was found to be disrupted by the translocation. Analysis of mRNA from CML ABL sequences are translocated from chro- mosome 9 to chromosome 22. This finding was the first direct demonstration of a reci- procal exchange between the two chromo- somes, and it indicated that ABL is involved in the generation of CML 5 . In 1983, Nora Heisterkamp showed that the ABL locus was adjacent to the breakpoint. With the help of colleagues, she cloned transloca- tion-associated sequences from both chromosomes 9 (ABL) and 22 (REF. 6). Janet Rowley reports the first translocation, t(8;21). Lore Zech associates t(8;14) with Burkitt?s lymphoma. Janet Rowley reports that the Ph chromosome is caused by t(9;22). Janet Rowley associ- ates the t(15;17) with acute promyelocytic leukaemia (APL). Cancer cytogeneticists convince clinicians of the relationship between chromosome transloca- tions and subtypes of leukaemia. Carlo Croce and Philip Leder carry out the first molecular characterization of a translo- cation. They use Southern blot analysis to show that t(8;14) disrupts the IGH and MYC genes. Third International Workshop determines the prognostic signifi- cance of chromosome abnormalities in acute lymphoblastic leukaemia (ALL). Claude Turc- Carel and Alain Aurias associate t(11;22) with Ewing sarcoma. Nora Heisterkamp and John Groffen clone the genes disrupted by t(9;22). Fourth International Workshop determines the prognostic signifi- cance of chromosomal abnormalities in acute myelogenous leukaemia (AML). David von Hansemann first observes mitotic aberrations in tumour cells. Theodor Boveri reports mitotic aberrations in tumour cells. Peter Nowell and David Hungerford associate the Ph chromosome with chronic myelogenous leukaemia (CML). Theodore Hauschka, Albert Levan and Sajiro Makino report that tumour cells have multiple chro- mosome aberrations. Timeline | History of the study of chromosome translocations in cancer Box 1 | Early cytogenetic analysis In the 1950s and 1960s, chromosomes were studied using Giemsa or Wright stains. With these techniques, chromosomes could be counted accurately and grouped together on the basis of similar size and shape, but they could not be distinguished within morphologically similar groups. In the 1970s, the development of chromosome banding allowed the precise identification of each chromosome and parts of chromosomes. There are several different banding techniques. a | The most commonly used is Giemsa banding (G-banding). G-banding requires pretreatment of cells with trypsin or heat, which removes proteins from chromatin. b | Chromosomes can also be stained with quinacrine mustard (Q-banding). Quinacrine binds preferentially to G+C-rich DNA, which is concentrated in dense chromosome bands that do not contain many genes. Q-banding does not require any type of pretreatment. After chromosomes are stained, they are examined under ultraviolet light and photographed. Individual chromosomes in photographs are cut out and rearranged by chromosome number. Arrows indicate the chromosomes 9 and 22 (Ph) affected by the translocation in CML patients. a 123 4 5 678 13 14 19 20 21 22 15 16 17 18 910112X b 123 45 678 13 14 19 20 21 22 15 16 17 18 910112X Emma Shtivelman identifies the BCR?ABL fusion mRNA. 1890 1914 1950s 1960 1972 1973 1976 1977 1978 1980 1982 1983 1984 1985 � 2001 Macmillan Magazines Ltd PERSPECTIVES a crucial aetiological component of these diseases. As more of the genes identified at translocation breakpoints were found to be oncogenes, molecular biologists began to study uncloned chromosome translocations, hoping to identify new cancer-related genes. The cloning of translocation breakpoints has proved to be one of the most efficient ways of identifying new genes that are involved in regulating cell growth and inducing malig- nant transformation (TABLE 1). For example, the discovery of the AML-associated 8;21 translocation (the first translocation identi- fied) 25 led to the identification of the gene that encodes the haematopoietic transcrip- tion factor AML1 on chromosome 21 (REF. 26). AML1, also known as core binding factor A2 (CBFA2 or RUNX1), binds DNA and het- erodimerizes with core binding factor B (CBFB), forming a stable complex that binds DNA more tightly 27 . The gene that encodes CBFB is located at 16q22 and is disrupted by the inv(16) chromosome abnormality 28 , which is associated with another type of acute myelomonocytic leukaemia (AML- oM4E) 29 . CBFA and B are now implicated in about 30% of all acute leukaemias. Over time, the perception of cytogenetics finally changed from the view that the field was an esoteric backwater with relatively little medical relevance to the realization that it is one of the principal tools for identifying genes involved in malignant transformation. In fact, leukaemia and lymphoma are now the most extensively characterized human malignant diseases 9 . All of the present evi- dence points to the fact that changes in gene function caused by translocations are crucial events in malignant transformation. We have identified almost 50 translocations that occur in over 1% of leukaemias, lymphomas or other solid tumours (BOX 2), and the genes affected by almost all of these common translocations have been cloned. specifically expressed by cancer cells made it an attractive therapeutic target. The develop- ment of the kinase inhibitor STI-571 almost two decades later has confirmed the wisdom of identifying oncogenes and searching for inhibitors. STI-571 has transformed CML therapy, and might also be useful in treating ALL when combined with other drugs 16 . The Philadelphia story is a scientific suc- cess story that began with the initial observa- tion of a chromosome abnormality and its identification as a translocation. This led to the molecular analysis of the genes involved, to the functional characterization of the genes and to the detection of their altered function due to the translocation, and finally to a drug that specifically targets the defective gene product. Hopefully, this model can be fol- lowed for the dozens of other translocations that are associated with human leukaemia, lymphoma, sarcomas and some benign tumours (ONLINE TABLE 1). First genetically defined translocation Although the Philadelphia chromosome was one of the first translocations to be discov- ered, the genes involved in the translocation that causes Burkitt?s lymphoma were the first to be molecularly characterized. In 1976, Lore Zech and colleagues analysed karyotypes of cells from Burkitt?s lymphoma patients, and observed that they contained an extra band at the distal region of the long arm of chromo- some 14, whereas the distal region at the long arm of chromosome 8 was missing 17 .They suggested a translocation between chromo- somes 8 and 14. It was not until 1982 that Carlo Croce and Bob Gallo showed that the human MYC oncogene was located on the region of chromosome 8 and was affected by the translocation 18 . This was the first onco- gene cloned at a translocation site. Simultaneously, Phil Leder?s group 19 showed that MYC was translocated into the 5? region of the immunoglobulin heavy chain (IGH) gene.This translocation, however, did not create a fusion protein, in the same way that the Philadelphia chromosome does. Instead, the translocation juxtaposes the IGH pro- moter region with the MYC coding sequences, resulting in abnormal timing and levels of MYC expression 20 . This transloca- tion is the most important component of the malignant transformation 21 . Interestingly, other lymphoid cancer- associated translocations also involve immune receptor genes, such as the 14;18 translocation, which is associated with fol- licular small cleaved-cell lymphoma 22 . This translocation juxtaposes the promoter region of IGH with the coding region of the anti-apoptotic protein BCL2 on chromo- some 18 (REF. 23). The anti-apoptotic func- tion of BCL2 was later identified by David Vaux and colleagues 24 , launching an enor- mous new field of cell biological and med- ical research. Malignant transformations can therefore be induced either by the juxtaposi- tion of a coding region from one gene with the promoter of another gene, or by fusion of two coding regions to create a new, chimeric gene that encodes a fusion protein (FIG. 1). Translocations that cause formation of a fusion protein are the most commonly reported, as they are associated not only with CML, but also with many acute leukaemias and sarcomas (ONLINE TABLE 1). The impact of molecular biology The association of particular chromosome translocations with subtypes of leukaemia and lymphoma helped to persuade haema- tologists and pathologists that chromosome abnormalities, especially translocations, were NATURE REVIEWS | CANCER VOLUME 1 | DECEMBER 2001 | 247 M.E. Huang uses all-trans retinoic acid (ATRA) to treat APL patients. Janet Rowley uses fluo- rescence hybridization to detect translocations. Brian Druker and Charles Sawyer show that STI-571, which targets the BCRr?ABL fusion protein caused by the chromosome 9?22 transloca- tion, can cure CML. Leukaemia, lymphoma Altered expression of gene B Expression of fusion proteins Gene A promoter Gene B coding region a b Gene A coding region Gene B coding region Figure 1 | The consequences of recurring chromosome translocations. a | In some lymphomas and leukaemias, chromosome translocations lead to the juxtaposition of promoter/enhancer elements from one gene (gene A, purple) with the intact coding region of another gene (gene B, red). b |By contrast, translocations seen in CML and many of the acute leukaemias result in recombination of the coding regions of two different genes. This results in a fusion protein that might have a new function. This is the case for the BCR?ABL fusion protein that is encoded by the Philadelphia chromosome. 1988 1990 1998 � 2001 Macmillan Magazines Ltd 248 | DECEMBER 2001 | VOLUME 1 www.nature.com/reviews/cancer PERSPECTIVES nisms that underlie most cancer-causing translocations, however, have not yet been determined 35 . Application to clinical medicine As more leukaemia patients underwent cyto- genetic analysis, clinicians found that the chromosome abnormalities were useful prognostic indicators 36,37 (BOX 2). The devel- opment of DNA probes that recognize translocation products has had an important impact on the field of pathology, because assays done with these probes do not require dividing cells, which are necessary for stan- dard cytogenetic analysis. Chromosomal translocations can now be identified using fluorescence in situ hybridization (FISH) of cytologic preparations, or through Southern blot analysis. Translocation sequences can also be detected using reverse transcriptase polymerase chain reaction (RT?PCR) and MULTIPLEX RT?PCR, which allows a sample to be screened for the presence of different translocations in parallel. Cytogeneticists have also created fluo- rescence probes that hybridize to whole chromosomes, to specific portions of chro- mosomes or to specific genes (FISH). These probes can be used to identify certain parts of chromosomes, such as centromeres, and to count the number of copies of each chromosome within tumour cells. A more recent technique ? known as spec- tral karyotyping (SKY) ? can be used to identify individual chromosomes and rearranged chromosomes (FIG. 2). This tech- nique has greatly improved our ability to identify chromosomal abnormalities in cancer cells. Many clinics now immediately carry out karyotyping on the cells of a leukaemia patient before treatment, as the identifica- tion of chromosome aberrations remains the best known way to predict how a patient will progress or respond to treatment. Some acute myelogenous leukaemia (AML)-asso- ciated translocations, such as t(8;21), t(15;17), and inversion 16 are associated with a positive response to treatment and long- term survival 38 . Conversely, a few transloca- tions ? such as those involving the MLL gene on chromosome band 11q23 ? are associated with poor prognosis. Similarly, in ALL patients, the presence of t(12;21) indi- cates a good prognosis, whereas the pres- ence of the Ph chromosome (the 9;22 translocation) indicates that the disease will advance rapidly. The importance of translocations in the classification of the leukaemias has been underscored by a recent report from the with these other genes 30 . This has been reported, for example, for the TCRA and HOX11 genes that are affected by the 10;14 translocation, which leads to T-cell ALL 32 . TCRA is the T-cell-receptor-? gene on chro- mosome 14, and HOX11 is a member of the homeobox family and is located on chro- mosome 10. Several studies have indicated that ALU sequences, a family of A+T-rich repeat sequences interspersed frequently throughout the genome, are involved in translocations 33 . The sequences have suffi- cient homology to pair, which leads to non- homologous recombination. Other studies report that TOPOISOMERASE II cleavage sites and DNASE I HYPERSENSITIVE SITES might be involved in recombination 34 . The precise mecha- However, we still do not understand the causes of chromosome translocations. Certainly some of them happen just by chance. There is also evidence from lym- phoid cells that some translocations occur due to an inappropriate use of DNA recom- bination mechanisms 30,31 . During T-cell and B-cell development, the genes that encode the immunoglobulin and the T-cell recep- tors undergo rearrangements. Enzymes that control recombination of these genes recog- nize signal sequences that activate recombi- nation. Some of the genes involved in translocations share the same signal sequences, and the recombinase machinery might erroneously use these signal sequences to recombine immune receptors Table 1 | Translocation-disrupted genes Class Gene Signal transducers Tyrosine kinases ABL, ALK, JAK2, LCK, PDGFRB Serine kinases BCR Surface receptors FGFR3, TAN1 Growth factor IL3 DNA-binding factors Homeobox HOX11, HOXA9, HOXD13, PBX1, PML, PMX1 Helix?loop?helix LYL1, MYC, TAL1, TAL2, TCF3 ETS factors ERG, ETV6, FLI1, MN1 Forkhead AF6q21, AFX, FKHR Zinc finger BCL6, ETO, EVI1, MLL, MOZ, PLZF, PML1, RARA, LIM LMO1, LMO2 Leucine zipper AF10, AF17 Other AF4, AF9, CBP/p300, DEK, E2F, ENL, LYT10, RUNX1 Other Septins CDC10rel, MSF Nucleoporins NUP98, NUP214 Transcriptional modulators BCL3, CBFB, ELL, NFKB2 Anti-apoptosis AP12, BCL2 RNA binding EWS, FUS, OTT, TLS/FUS Box 2 | How many cancer-associated translocations are there? We do not have an accurate number, but the chromosome abnormalities that are present in at least several patients (and are therefore considered to be recurring abnormalities) are included in a catalogue of cancer chromosome abnormalities 44 . The largest number of chromosomal aberrations have been associated with haematological disorders, but many have also been associated with mesenchymal and epithelial tumours. This catalogue began as a journal article, became a printed catalogue and now is available online (see online links box). The catalogue is maintained by the Mitelman group in Sweden, as well as the National Cancer Institute 41 . This database is important because a cytogeneticist can refer to it to determine whether the abnormalities seen in a patient are unique or have been previously reported, and to learn about the clinical features and outcome. A molecular geneticist interested in cloning a particular breakpoint can also use the database to find appropriate patients and material for genetic analysis. � 2001 Macmillan Magazines Ltd PERSPECTIVES from healthy individuals 41 . There have not been any known follow-up studies of these individuals, however, to determine whether these cells ever became malignant. But togeth- er, these data provide evidence that the pres- ence of a translocation is not in itself sufficient for a fully malignant phenotype. Nevertheless, the fact that STI-571 is an effective CML ther- apy would argue that, even if it is not suffi- cient, the BCR?ABL fusion is necessary for the malignant phenotype. Future directions The karyotypes of malignant cells have pro- vided us with a wealth of information about the genetic and molecular basis of cancer. We have been successful in identify- ing genes that become disrupted by chro- mosome translocations, but considerably less successful in identifying the genes that are lost in chromosome deletions. For example, a deletion in the long arm of chro- mosome 5 is associated with AML ? espe- cially in individuals who have received pre- vious mutagenic therapy 42 . Although this deletion has been studied for almost two decades 43 and occurs in a sequenced, gene- rich region, the gene or genes that are dis- rupted by this deletion are still unknown. Chromosome deletions are a particularly interesting area of genetic research, as they are frequently accompanied by transloca- tions or other complex chromosome abnormalities. We have also been unsuc- cessful in identifying the genes that are affected by chromosome amplification, except for cases in which the genes are present in dozens of copies. World Health Organization 9 , in which some of the leukaemia categories are identified solely by cytogenetics. Cytogenetic characteri- zation has therefore replaced morphological analysis in the classification of some leukaemias 9 . Translocation type is crucial in determining the most appropriate therapy. For example, an acute promyelocytic leukaemia patient that carryies the t(15;17) is likely to respond to therapy with all-trans retinoic acid 39 , whereas cells from a CML patient that carries t(9;22) are likely to express the BCR?ABL fusion protein, and can be treated with STI-571 (REF. 16). Cytogenetics can also be used to monitor the response of a patient to therapy. REAL-TIME RT? PCR can be used throughout a patient?s treatment pro- gramme to monitor the proportion of leukaemic cells that still carry a translocation- induced fusion mRNA. Malignancy is a multistep process and translocations by themselves are probably, at least in general, not sufficient to induce a fully malignant phenotype. AML patients who carry t(8;21) can remain in complete remission (off treatment) for more than 8 years, even though their peripheral blood still contains AML?ETO + cells 40 . In addition, there are several studies that report the detection of chromosome translocations in cells taken NATURE REVIEWS | CANCER VOLUME 1 | DECEMBER 2001 | 249 17 715X 513 der(17), t(17;16;X) der(5), t(5;12) der(13;15), t(20;13;Y;15) der(7)del(7), t(7;15) der(15), t(15;21), dic(15;19), t(7;15;22;19) der(X), t(X;5) abc Figure 2 | Chromosome rearrangements in acute myeloid leukaemia cells. Metaphase cells from an untreated acute myelogenous leukaemia (AML) patient were analysed using spectral karyotype (SKY) analysis. a | The chromosomes were first stained with a mixture of labelled probes specific for different chromosomes. Normal chromosomes are uniform in colour, whereas rearranged chromosomes show two or more colours (arrows). b | The spectral pattern of chromosomes has been classified using computer software to identify individual chromosomes. Each chromosome has its own colour code. Several colours on a single chromosome indicate a rearrangement. c | Presentation of rearranged chromosomes. Each separate panel shows the spectral and classified images of the normal parent chromosome (left two chromosomes), and the spectral and classified images of the rearranged chromosome (right two chromosomes). The analysis of each chromosome type is listed below, including the chromosome that the rearrangement is derived from (der). In this cell, rearrangements are caused by translocations (t), deletions (del), or dicentric chromosomes (dic). For example, for chromosome 13 (upper right panel), the rearrangements include pieces of chromosome 15, the Y chromosome, chromosome 13 and chromosome 20, from the top to bottom. There are at least 30 separate rearrangements in this cell. Each is not necessarily associated with a cancer. Glossary DICENTRIC CHROMOSOME A chromosome that has two centromeres, formed by breakage and reunion of two chromosomes. DNASE I HYPERSENSITIVE SITE DNA sites that are open and accessible to cleavage by DNA-specific enzymes. MULTIPLEX RT?PCR Primers for several mRNAs are used in a single RT?PCR reaction, allowing amplification of many (6 ?12) separate RNA templates. This technique can be used to screen cells for several translocations at once. REAL-TIME RT?PCR RT?PCR using a fluorescent probe that contains a 5?- fluorescent label and 3?-quencher dye. As reverse tran- scription occurs, the 5?-reporter dye is released and the level of fluorescence emission can be measured as the reaction is proceeding. This technique can be used throughout a patient?s treatment programme to moni- tor the proportion of leukaemic cells that still carry a translocation-induced fusion mRNA. RT?PCR (Reverse transcriptase polymerase chain reaction). This technique can be used to amplify cDNA from an mRNA template, using sequence-specific primers. Primers for fusion mRNAs created by known chromo- some translocations can be used to identify cancer cells. RING CHROMOSOME Two breaks occur in the same chromosome, on opposite sides of the centromere. In these chromosomes, the ends of the centric fragment fuse. SOMATIC CELL HYBRID Fusion of cells from two species, often rodent and human. This causes loss of chromosomes, reducing the number of chromosomes from one species. These were important early tools used for mapping the location of genes to chromosomes. TOPOISOMERASE II An enzyme that binds to double-stranded DNA, cleaves both strands, passes one strand through the other to unwind the DNA and then relegates the broken ends. � 2001 Macmillan Magazines Ltd 250 | DECEMBER 2001 | VOLUME 1 www.nature.com/reviews/cancer PERSPECTIVES 16. Druker, B. J. et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N. Engl. J. Med. 344, 1038?1042 (2001). 17. Zech, L., Haglund, U., Nilsson, K. & Klein, G. Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Burkitt and non-Burkitt lymphomas. Int. J. Cancer 17, 47?56 (1976). 18. Dalla-Favera, R. et al. Human c-MYC onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl Acad. Sci. USA 79, 7824?7827 (1982). 19. Taub, R. et al. Translocation of the c-MYC gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc. Natl Acad. Sci. USA 79, 7837?7841 (1982). 20. ar-Rushdi, A. et al. Differential expression of the translocated and the untranslocated c-MYC oncogene in Burkitt lymphoma. Science 222, 390?393 (1983). 21. Adams, J. M. et al. The c?Myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 6046 (1985). 22. Fukuhara, S., Rowley, J. D., Variakojis, D. & Golomb, H. M. Chromosome abnormalities in poorly differentiated lymphocytic leukemia. Cancer Res. 39, 3119?3128 (1979). 23. Tsujimoto, Y., Finger, L. R., Yunis, J., Nowell, P. C. & Croce, C. M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science 266, 1097?1099 (1984). 24. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-Myc to immortalize pre-B cells. Nature 335, 440?442 (1988). 25. Rowley, J. D. Identification of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann. Genet. 16, 109?112 (1973). 26. Miyoshi, H. et al. The t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia clustered within a limited region of a novel gene, AML1. Proc. Natl Acad. Sci. USA 88, 10431 (1991). 27. Wang, Q. et al. The CBF? subunit is essential for CBF?2 (AML1) function in vivo. Cell 87, 697?708 (1996). 28. Le Beau, M. M. et al. Association of inv(16)(p13q22) with abnormal marrow eosinophils in acute myelomonocytic leukemia: a unique cytogenetic- clinicopathologic association. N. Engl. J. Med. 309, 630?636 (1983). 29. Liu, P. et al. Fusion between transcription factor CBF?/PEBP2? and ? myosin heavy chain in acute myeloid leukemia. Science 261, 1041?1044 (1993). 30. Finger, L. R., Harvey, R. C., Moore, R. C., Showe, L. C. & Croce, C. M. A common mechanism of chromosomal translocation in T and B cell neoplasia. Science 234, 982?985 (1986). 31. Rabbitts, T. H., Boehm, T. & Mengle-Gaw, L. Chromosomal abnormalities in lymphoid tumors: mechanism and role in tumor pathogenesis. Trends Genet. 4, 300 (1988). 32. Hatano, M., Roberts, C. W., Minden, M., Crist, W. M. & Korsmeyer, S. J. Deregulation of a homeobox gene, HOX11, by the t(10;14) in the T cell leukemia. Science 253, 79 (1991). 33. Schichman, S., Canaani, E. & Croce, C. M. Self-fusion of the ALL-1 gene: a new genetic mechanism for acute leukemia. J. Am. Med. Assoc. 273, 571?576 (1995). 34. Strissel, P. A. et al. DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis. Hum. Mol. Genet. 9, 1671?1679 (2000). 35. Stanulla, M., Wang, J., Chervinsky, D. S., Thandla, S. & Aplan, P. D. DNA cleavage within the MLL breakpoint It is important to gain a better under- standing of the full genetic and molecular effects of chromosome rearrangements, as this is one of the best routes to developing cancer-specific designer drugs. One of the lessons learned from the STI-571 story is that going from genotype to therapy requires a diverse group of scientists, along with the support of industrial research. Although the financial rewards for industry might not be great, the important thing ? the therapeutic benefits ? are immeasurable. Janet D. Rowley is at the Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 2115, Chicago, Illinois 60637, USA. e-mail: jrowley@medicine.bsd.uchicago.edu 1. Boveri, T. in Zur Frage der Entstehung maligner Tumoren (Gustav Fischer, Jena, 1914). 2. Levan, A. Some current problems of cancer cytogenetics. Hereditas 57, 343?355 (1967). 3. Nowell, P. & Hungerford, D. A minute chromosome in human granulocytic leukemia. Science 132, 1497 (1960). 4. Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243, 290?293 (1973). 5. de Klein, A. A. Cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature 300, 765?767 (1982). 6. Heisterkamp, N. et al. Localization of the c-ABL oncogene adjacent to a translocation breakpoint in chronic myelocytic leukemia. Nature 306, 239?242 (1983). 7. Groffen, J. et al. Philadelphia chromosomal breakpoints are clustered within a limited region, BCR, on chromosome 22. Cell 36, 93?99 (1984). 8. Shtivelman, E., Lifschitz, B., Gale, R. P. & Canaani, E. Fused transcript of ABL and BCR genes in chronic myelogenous leukaemia. Nature 315, 550?554 (1985). 9. Jaffe, E. S., Harris, N. L., Stein, H. & Vardiman, J. W. (eds) World Health Organization Classification of Tumours, Pathology and Genetics: Tumours of the Hematopoietic and Lymphoid Tissues (IARC, Lyon, 2001). 10. Berger, R., Chen, S. J. & Chen, Z. Philadelphia-positive acute leukemia. Cytogenetic and molecular aspects. Cancer Genet. Cytogenet. 44, 143?152 (1990). 11. Hermans, A. et al. Unique fusion of BCR and c-ABL genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell 64, 343 (1987). 12. Witte, O. N., Dasgupta, A. & Baltimore, D. Abelson murine leukemia virus protein is phosphorylated in vitro to form phosphotyrosine. Nature 281, 396?398 (1980). 13. Konopka, J. B., Watanabe, S. M. & Witte, O. N. An alteration of the human c-ABL protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 37, 1035?1042 (1984). 14. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Induction of chronic myelogenous leukemia in mice by the p210 BCR/ABL gene of the Philadelphia chromosome. Science 247, 824 (1990). 15. Fialkow, P. J. in Genes and Cancer (eds Bishop, J. M., Rowley, J. D. & Greaves, M.) 215?226 (Alan R. Liss, New York, 1984). cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. Mol. Cell. Biol. 17, 4070?4079 (1997). 36. Mitelman, F. The Third International Workshop on Chromosomes in Leukemia. Lund, Sweden, July 21?25, 1980. Introduction. Cancer Genet. Cytogenet. 4, 96?98 (1981). 37. Bloomfield, C. D., Goldman, A., Hossfeld D. & de la Chapelle, A. Fourth International Workshop on Chromosomes in Leukemia 1982: clinical significance of chromosomal abnormalities in acute nonlymphoblastic leukemia. Cancer Genet. Cytogenet. 11, 332?350 (1984). 38. Grimwade, D. et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children?s Leukaemia Working Parties. Blood 92, 2322?2333 (1998). 39. Huang, M. E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567?572 (1988). 40. Nucifora, G. & Rowley, J. D. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86,1?14 (1995). 41. Uckun, F. M. et al. Clinical significance of MLL-AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation. Blood 92, 810?821 (1998). 42. Rowley, J. D., Golomb, H. M. & Vardiman, J. W. Nonrandom chromosomal abnormalities in acute nonlymphocytic leukemia in patients treated for Hodgkin?s disease and non-Hodgkin lymphomas. Blood 50, 759?770 (1977). 43. Zhao, N. et al. Molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases to 1?1.5 Mb and preparation of a PAC- based physical map. Proc. Natl Acad. Sci. USA 94, 6948?6953 (1997). 44. Mitelman, F. Catalog of Chromosome Aberrations in Cancer 5th edn (Wiley?Liss, New York, 1994). 45. Olney, H.J., Gozzetti, A., & Rowley, J.D. in Hematology of Infancy and Childhood 6th edn (eds. Nathan, D., Orkin, S., Look, T. & Ginsburg, D. (WB Saunders, Philadelphia, 2002, in the press). 46. Chaganti, R., Nanjangud, G., Schmidt, H. & Teruya- Feldstein, J. Recurring chromosomal abnormalities in non-Hodgkin's lymphoma: biologic and clinical significance. Sem. Hematol. 37, 396?411 (2000). Acknowledgements The research from my laboratory described in this paper was supported by the National Cancer Institute and the G. Harold and Leila Y. Mathers Foundation. I thank H. Olney, Y. Kobzev and S. Maaskant for their valuable assistance. Online links DATABASES The following terms in this article are linked online to: CancerNet: http://cancernet.nci.nih.gov/ acute lymphoblastic leukaemia | acute myelocytic leukaemia | chronic myelogenous leukaemia LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/ Abl | ABL | AML1 | BCL2 | BCR | CBFA | CBFB | ETO | HOX11 | IGH | MLL | MYC | TCRA Medscape DrugInfo: http://promini.medscape.com/drugdb/search.asp Glivec FURTHER INFORMATION F. E. Mitelman Database of Chromosome Aberrations in Cancer: http://cgap.nci.nih.gov/Chromosomes/Mitelman Access to this interactive links box is free online. "
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