ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 13, No. 2 Copyright © 1983, Institute for Clinical Science, Inc.
Chromosome Abnormalities in Leukemia and Lymphoma JANET D. ROWLEY, M.D. Department o f Medicine, University o f Chicago, Chicago, IL 60637
ABSTRACT Nonrandom chromosome changes have been identified in a number of malignant human tumors. The leukemias are among the best studied malignant cells and they provide the largest body of relevant cytogenetic data. In chronic myeloid leukemia, a reasonably consistent translocation [t(9;22) (q34;qll)] is observed in 93 percent of all Ph1 positive patients. In the other patients, translocations are either two-way, involving No. 22 with some other chromosome or complex translocations involving Nos. 9 and 22 and another chromosome. In acute nonlymphocytic leukemia, two translo cations are each specifically associated with leukemic cells arrested at two different stages of maturation. One of these, t(8;21)(q22;q22), is found mainly in patients with acute myeloblastic leukemia with maturation (AML-M2). The other, t(15;17)(q22?;q21?), is seen only in patients with acute promyelocytic leukemia (APL-M3). Various translocations have been observed in B-cell acute lymphoblastic leukemia or in Burkitt lymphoma. The most common is t(8;14)(q24;q32), but variants of this, nam ely t(2;8)(pl3?;q24) and t(8;22)(q24;qll), have also been observed; in all of these, the consistent change involves 8q24. The various immunoglobulin loci are located on chromosomes 2, 14, and 22 in the same chromosome band affected by the translocations in B-cell leukemia. These translocations may occur randomly. If a specific translocation pro vides a particular cell type with a growth advantage, then selection could act to cause the proliferation of this aneuploid cell line vis-a-vis cells with a normal karyotype. In this view, the chromosome change could be the fun damental event leading to the leukemic transformation of an otherwise normal cell. The challenge for the future is to define the genes located at the sites of consistent translocations in myeloid leukemias and to deter mine the alterations in gene function that are associated with the transloca tion. Introduction
exciting areas in cancer research over the last 20 years. Major advances in our un The study of the chromosome pattern derstanding of the specificity of some of in the affected cells of a num ber of the abnormalities have occurred in the human tumors has been one of the most last ten years with the application of new 87 0091-7370/83/0300-0087 $01.20 © Institute for Clinical Science, Inc.
chromosome banding techniques. These techniques allow the identification of each human chromosome and of parts of chromosomes as well. Thus, the hypothe sis put forward by Boveri, that an abnor mal chromosome pattern was intimately associated with the malignant phenotype of the tumor cell, can now be tested with substantial hope of obtaining a valid an swer.6 The study of chromosome pattern in human leukemias can be divided into two ten-year periods, 1960 to 1970 and 1970 to 1980. During the first period, the chrom osom e abnorm alities seen in leukemic cells were identified without banding. The most significant observa tion was the identification of the Phil adelphia (Ph1) chromosome in leukemic cells from patients with chronic myelog enous leukemia. This abnormality, dis covered by Nowell and Hungerford,23 appeared to be a deletion of about onehalf of the long arm of one G group chromosome either No. 21 or No. 22. The search for sim ilar abnorm alities as sociated with other malignant hematolog ic diseases was disappointing. Leukemic cells in about one-half of the patients with acute leukemia appeared to have a normal karyotype.27'33 Thus the accepted notion was that the Ph1 was a unique example of a consistent karyotypic abnor mality, and the general rule was one of marked variability in karyotype. The evidence obtained during the sec ond period showed that this notion was incorrect. With the use of banding tech niques, other specific abnormalities were found to be associated w ith certain leukemias and lymphomas.27 Moreover, banding techniques revealed that the gains and losses of chromosomes were distinctly nonrandom. It should be em phasized that the data presented here have been gathered primarily during the period 1974 to 1982. Most of the studies during this period used chromosomes that w ere relatively contracted, and the banding pattern often was fuzzy and
poorly defined. T hus, subtle abnor malities such as a deletion or a duplica tion of one-third of a chromosome band, involving about 3 x 10® nucleotide pairs, would be undetectable. A third period of analysis is now being embarked upon that will be characterized by substantial improvements in the qual ity of the chromosome preparations that are available for analysis. Yunis et al38 have recently reported that with the use of elongated (prophase) chromosomes from bone marrow cells of patients with acute nonlymphocytic leukemia (ANLL) everyone of 24 patients had an abnormal karyotype. Thus, the future emphasis will be to identify the abnormalities that have been overlooked in the past. Methods and Nomenclature An analysis of chromosomal patterns, to be relevant to a malignant disease, must be based on a study of the karyotype of the tumor cells themselves. In the case of leukemia, the specimen is usually a bone marrow aspirate that is processed imme diately or cultured for a short time.35 In patients with a white blood cell count higher than 15,500, with about 10 percent im m ature m yeloid cells, a sam ple of peripheral blood can be cultured for 24 or 48 hours without adding phytohemagglu tinin (PHA). The karyotype of the divid ing cells will be similar to that obtained from the bone marrow. It is more difficult to obtain chromosomes from lymph nodes or spleen; however, careful attention to the details of tissue culture can provide mitotic cells in about 85 percent of the samples in our laboratory. Lymph node cells are usually processed directly or are cultured for only 24 to 48 hours before chromosome preparations are made. When an abnormal karyotype is found in a tumor, it is important to analyze cells from normal tissues, such as skin fibro blasts or peripheral blood lymphocytes stimulated to divide with the addition of PHA. In most instances, cells from these
in human cancer. They observed an un usually sm all G -group chrom osom e, which appeared to have lost about onehalf of its long arm, in leukemic cells from patients with chronic myelogenous leukemia (CML). Chromosome banding techniques were first used in the cyto genetic study of leukemia for identifi cation of the Ph1 chromosome as a de letion of No. 22 (22q—). Since quinacrine fluorescence revealed that the chromo some present in triplicate in Down’s syn drome was No. 21, the abnormalities in Down’s syndrome and CML were shown to affect different pairs of chromosomes. The question of the origin of the Ph1 (22q—) was answered when Rowley24 re ported that the Ph1 chromosome results from an apparently balanced reciprocal translocation (9;22)(q34;qll) rather than a deletion as many investigators had pre viously assumed. Karyotypes of 1129 Ph'+ patients with CML have been examined with banding techniques by a number of investigators, and the 9;22 translocation has been iden tified in 1036 (92 percent).31 It is now recognized that, in addition to the typical t(9:22), variant translocations may oc cur.21,33 These appear to be of two kinds: one is a simple translocation involving No. 22 and some chromosome other than No. 9, which has been seen in 42 pa tients. The other is a complex transloca tion involving three or more different chromosomes; except in two cases, two of the chromosomes involved were found to be No. 9 and No. 22. This type of translo cation has been observed in 46 patients. Five patients have been reported who are said not to have had a translocation. The great specificity of the translocation in volving Nos. 9 and 22 remains an enigma. The survival curves for patients w ith variant translocations appeared to be the same as those for patients with the stan dard t(9;22). C h r o n ic P h a s e Acute Phase o f Chronic Myelogenous Nowell and Hungerford23 reported the Leukemia. W hen patients w ith CML first consistent chromosome abnormality enter the terminal acute phase, about 20 unaffected tissues will have a normal karyotype. The chrom osom e abnor malities observed in the tumor cells thus represent somatic mutations in an other wise normal individual. The observation of at least two “pseudodiploid” or hyperdiploid cells or three hypodiploid cells, each showing the same abnormality, is considered evi dence for the presence of an abnormal clone; patients with such clones are clas sified as abnormal. Patients whose cells show no alterations, or in whom the alter ations involve different chromosomes in different cells, are considered to be nor mal. Isolated changes may be due to technical artifacts or to random mitotic errors. In malignancies with a very low mitotic index, however, a single abnor mal cell may be the only malignant cell undergoing mitosis. In the following discussion, the chro mosomes are identified according to the international system for human cytoge netic nomenclature (1978),11 and the karyo types are expressed as recom m ended under this system. The total chromosome number is indicated first, followed by the sex chromosome, and then by the gains, losses, or rearrangem ents of the autosomes. A + sign or —sign before a num ber indicates a gain or loss, respectively, of a whole chromosome; a + or — after a number indicates a gain or loss of part of a chromosome. The letters “p” and “q” refer to the short and long arms of the chrom osome, respectively. Transloca tions are identified by “t” followed by the chromosomes involved in the first set of brackets; the chromosome bands in which the breaks occurred are indicated in the second brackets. Uncertainty about the chromosome or band involved is sig nified by “?”. Chronic Myelogenous Leukemia
percent appear to retain the 46, Ph1-!- cell line unchanged, whereas other chromo some abnormalities are superimposed on the PhH cell line in 80 percent of pa tients.26 In a number of cases, the change in the karyotype preceded the clinical signs of blast crisis by two to four months. In general, if patients have a clone of Ph*+ cells with a unique marker during the chronic phase, this clone will be the one involved in the transformation. Bone marrow chromosomes from 379 patients with Ph1 + CML, who were in acute phase, have been analyzed with banding techniques.26 Seventy-six showed no change in their karyotype, whereas 303 patients had additional chromosome abnormalities. The most common changes frequently occur in combination to pro duce modal numbers of 47 to 52. The fol lowing gains or structural rearrange ments of particular chromosomes were observed in 303 patients who had rela tively complete analyses: gain of No. 8, 119 patients; gain of an isochromosome No. 17q, 79 patients; gain of No. 19, 45 patients; and gain of Ph1, 113 patients. Specific Translocations in Acute Nonlymphocytic Leukemia The recognition of nonrandom gains and losses of chromosomes (notably +8 and —7) was one of the important obser vations in the study of acute nonlym phocytic leukemia (ANLL) with the use of banding techniques. The identification of specific chromosome translocations as sociated w ith m aturation arrest of granulocytes at a particular stage in dif ferentiation remains a fascinating phe nomenon, the significance of which is currently unknown.
likely representing a translocation be tween C- and a G-group chromosome. The exact nature of this abnormality was resolved by Rowley25 who determ ined that it was a balanced translocation be tw een chromosomes 8 and 21 [t(8;21) (q22;q22)]. The frequency with which this translocation occurs seems to vary but it is about ten percent of the abnor mal cases of ANLL. The abnormality ap pears to be largely restricted to patients with a diagnosis of M2 (acute myeloblas tic leukem ia [AML] w ith maturation) according to the French-American-British (FAB) classification.1 At the Fourth International W orkshop on C hrom o somes in Leukem ia,10 of cases w ith a t(8;21) and adequate bone marrow ma terial available for cytological review, all except four had a diagnosis of M2; the exceptions appeared to be M4. The 8;21 translocation is also of inter est for two other reasons. First, chromo somes 8 and 21 can participate in threeway rearrangements similar to those in volving chromosomes 9 and 22 in CML. Lindgren and Rowley15 reported on two patients with three-way translocations in whom the third chromosome was either a No. 11 or a No. 17. Second, the t(8;21) is often accompanied by the loss of a sex chromosome; of the cases reviewed at the Fourth International W orkshop on Chromosomes in Leukemia,10 85 percent of the males with the t(8;21) were —Y and 50 percent of the females were missing one X. This association is particularly noteworthy because sex chromosome ab normalities are otherwise rarely observed in ANLL. T h e 15; IV T r a n s l o c a t io n a n d A c u t e P r o m y e l o c y t ic L e u k e m ia
A structural rearrangement involving chromosomes 15 and 17 in acute pro myelocytic leukemia (APL) was first recog In 1968, Kamada et al12 recognized that nized by Rowley et al.30 The breakpoint a subgroup of ANLL patients may be in No. 15 appears to be distal to band q21, characterized by an abnorm ality most and in No. 17 it appears to be in q21 T h e 8;21 T r a n s l o c a t io n in A c u t e M y e l o b l a s t ic L e u k e m ia
[t(15;17)(q2200;q2100)(14). O f the 82 pa tients with APL who were reviewed at the Fourth Workshop,10 50 had a t(15;17) alone (37 cases) or with other abnor malities; four had other types of chromo some changes; and 28 had a norm al karyotype. The rearrangem ent was not found in patients with any other type of leukem ia. Two cases w ith com plex translocations involving Nos. 15 and 17 and either No. 2 or No. 3 were recently reported.5 Thus, the same pattern of vari ation of a specific translocation can in volve the t(15;17) as well as the t(9;22) and the t(8;21). In some cases, the granules typically seen in the leukemic promyelocytes may be too small to be seen by light micros copy, although they are present when the cells are exam ined ultrastructurally.34 The FAB Co-operative Group recently recognized that not all APL patients have coarse granules and has thus added a cat egory called the M3 variant.2 The variant category was identified largely on the basis of the clinical features and the pres ence of the t(15;17). These translocations are unusual in that the incidence of both is much higher in children and in young adults than is true for other karyotypic abnormalities in ANLL. Thus, the m edian age for the t(8;21) is 45 years and for the t(15;17) is 25 years.14 Neither translocation has been reported in other types of human cancer. It is also of interest that the t(8;21) has never been reported as a constitutional abnormality and the t(15;17) has been re ported only once.9 W hether or not the breakpoints in the constitutional translo cation are similar to those seen in APL has not yet been established. Consistent Translocations in Burkitt Lymphoma and in B-Cell Acute Lymphocytic Leukemia.
study of samples has revealed a com plexity in the karyotype which was not suspected on the basis of the initial re ports. Fresh tumor tissue obtained from six patients with African Burkitt lym phom a was studied w ith quinacrine banding by Manolov and M anolova.17 They reported on the presence of an extra band at the end of the long arm of one chromosome No. 14 (14q+) in five of the six tumors, and in five of six cell lines es tab lish ed from tum ors from other patients. Zech et al39 reported that the material at the end of No. 14 represented a translocation from the end of No. 8 [t(8;14)(q24;q32)] in eight of the 10 Afri can Burkitt tumors in which it could be scored; two other tumors had the 14q+ chromosome, but the fluorescence was inadequate and involvem ent of No. 8 could not be determined. These obser vations have since been confirmed by others. T he t(8;14) is found in non endemic as well as in tumors from en demic areas. Moreover, it is present in those that are Epstein-Barr virus (EBV) positive and those that are EBV negative. Recently, Manolova et al18 examined more elongated chromosomes from five Burkitt lymphoma cell lines. They de termined that the break in No. 8 is in the proximal pale portion of band 8q24; in No. 14, it is the distal part of 14q32 in every case. The heterogeneity of the translocation in Burkitt lymphoma has only recently been recognized. There are now several patients with non-African Burkitt lym phoma whose cells show a translocation involving the short arm of No. 2 and the long arm of No. 8 [t(2;8)(pl2;q24)].22,37 Patients have been reported who have a second variant translocation, nam ely t(8;22)(q24;qll).3 Thus, the consistent change in all three translocations is the involvement of band 8q24. The data are too preliminary to determine whether or B u r k it t L y m p h o m a not there are important differences in the B urkitt lym phom a is an excellent biological behavior of the Burkitt cells example of a disease in which continued with translocations other than t(8; 14).
Although the variants were originally re Com plete karyotypes were available ported in non-African Burkitt lympho for only some of the 35 chromosomally mas, subsequent study has detected the abnormal patients, and the changes ap same variants in tumors of African origin.4 peared to be somewhat variable; some changes, however, occurred more often than others, the predominant one being B - C e ll A c u t e L y m p h o c y t ic L e u k e m ia the 14q+ chromosome. A 14q+ chromo An apparently identical 8; 14 transloca some was identified in 24 of the 35 pa tion has been observed in acute lympho tients in whom chromosomally abnormal cytic leukemia (ALL) patients with B-cell cells w ere found. A translocation b e markers and in patients with L3-type tween No. 14 and No. 18 was the most leukemic cells,20 indicating that Burkitt com m on one noted, and recent data lymphoma and most B-cell ALL of the suggest that it may occur in more than L3 type are probably different manifesta one-half of all PDL patients.* tions of the same disease. Sixteen pa tients with this rearrangement were re D if f u s e H is t i o c y t i c L y m p h o m a ported at the Third International Work shop on C hrom osom es in L eukem ia Chromosome analyses with the use of (1981).36 In one patient with this translo banding have been performed on 32 pa cation, the leukemic cells had a pre-B- tients with diffuse histiocytic lymphoma cell phenotype and were of the LI type;13 (DHL).28 In most cases, the analysis was the morphology of the leukemic cells, done on involved lymph nodes or tissue however, changed to L3-type at relapse. from extra-nodal sites, although cells Recently, one of the same variant translo from pleural or ascitic fluid or circulating cations that were described in Burkitt cells in the leukemic phase were also lymphoma has been identified in B-cell used. Every patient had a chromosomally ALL. This was a t(2;8) found in ALL pa abnormal clone of cells; in a few patients, two different, but related clones, were tient with the L3 type.32 observed. The chromosome pattern in some pa Karyotype in other tients was extremely complex, with 15 Non-Hodgkin Lymphoma or more structurally rearranged chromo P o o r l y D if f e r e n t ia t e d somes per cell. Under these circumstances, L y m p h o c y t ic L y m p h o m a correct identification of all the breaks and rearrangements becomes very difficult. Partial or complete data on the chromo Some valid conclusions can neverthe some analysis are available for 38 pa less be reached at this time, based on tients with poorly differentiated lympho data from 28 patients in whom the analy cytic lymphoma (PDL).29 Among the 38 sis was sufficiently complete to give fair patients, cytogenetic analysis was per ly adequate information. The single most formed on a clearly involved specimen common abnormality was a translocation (lymph nodes or effusions) in 27; peri to the end of the long arm of No. 14, pheral blood was studied in the remainder. usually to band 14q32; this occurred in W ith one exception, a chromosomally 15 patients. The donor chromosome in abnormal clone was obtained from speci volved in the translocation tended to be mens that contained m alignant cells, variable. i.e., lymph nodes or effusions. In more than one-half of the lymph nodes, 12 to 50 percent of the cells had a normal karyotype. * Rowley, unpublished data.
Implications of Nonrandom Changes for Malignant Transformation The evidence presented demonstrates that nonrandom chromosome changes are closely associated w ith a variety of human hematologic disorders. Similar as sociations have been identified in other human tumors and in animal tumors as well.28 The changes consist of gains or losses of part or all of certain specific chromosomes and of structural abnor malities, most frequently relatively con sistent translocations, that are presumed to be reciprocal. The nonrandom translo cation observed by us in malignant cells would represent those that provide a particular cell type with a selective ad vantage vis-a-vis in the cells with a nor mal karyotype. There is very strong evi dence that many malignancies, CML and Burkitt lymphoma, for example, are of clonal origin. This means that a particular translocation in a single cell gives rise to the tumor or to the leukemia that ulti mately overwhelms the host. Other rear rangements may be neutral, and the cells, therefore, will survive but will not prolif erate differentially; still others may be lethal and thus would be eliminated. In such a model, the chromosome change is fundamental to malignant transformation. The new data regarding the location of certain genes provides clues as to the nature of the genes that are affected by translocations. This evidence is most clear for the various translocations seen in Burkitt lymphoma and B-cell ALL. The m ost com m on translocation is t(8;14), but two variants, t(2;8) and t(8;22) are also observed. It is certainly signifi cant that the gene for the immunoglobu lin heavy chain is located on chromo some 14,7 while the gene for the lambda light chain is on No. 22,8 and for the kappa light chain is on 2p.16,19 Thus, each one of the various different chromosomes that is involved in a translocation with No. 8 carries a gene that would be of great importance in the normal function of a
B-cell. What the role of 8q is in modifying this function so that the cell becomes a malignant B-cell is presently unknown. It seems almost certain, however, that the involvem ent in these translocations of the chromosomes carrying various im munoglobulin genes is not fortuitous. The main stumbling block to making the same kinds of correlations for the consistent translocations seen in myeloid cells is our lack of understanding of which of the biologic markers currently under investigation has an analogous functional role in myeloid cells. It may be possible to work backward in myeloid cells by first defining the genes that are present at the sites of specific transloca tions and then determining the changes in gene function observed in myeloid cells with and without the translocation. Acknowledgments The results presented in this review were ob tained during research supported in part by the De partment of Energy—No. DE-AC02-80EV10360 and grants supported by PHS Grant numbers CA16910, CA-19266, CA-23954, and CA-25568 awarded by the National Cancer Institute, DHHS.
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N ow ell,