Mechanisms of chromosome translocation in B- and T-cell neoplasia

TIG [ 3 ] - ]anuc~y 1987

review Mechanisms of chromosome translocation in B-and T-cell neoplasia:

The first description of a tumor-specific chromosome aberration, the Philadelphia chromosome in cl'xonic myeIogenous leukemia, led to the general realization that most cancers display characteristic cytogenetic abnormalities. Frank G. Haluska, Yoshihide Tsujimoto and With the advent of high ,~esolution chromosome banding techCarlo M. Croce niques, somatic cell genetic techniques, and new methods Studies on tie molecular features of non-random chromosome translocalions of for in siiu hybridization of ~rmphaid maligaa~i~ have revealed that e~wymes which normally eatalyse the molecular probes and intact recombination of immunoglobulin and T.cell receptor genies may cause specific tvanslocations. The type of mechanism implicated in the translocation, coupled chromosomes, many of these with other ~pec~s of the tumor phenotype, allow us to specify the point in ram-random chromosome aberb,mphocyte ontoger,y at tehich the event leading to neoplastic tra~formalion rations have been precisely occurred. dlaracterized cytogenetically. IrLcreasingiy, these chromosome abnormalities have fallen within the purview of chromosomes 11 or 14, derive from neither. (4J On molecularbiology. At this level, we may ask: what is the chromosome 11, sequences are observed that have rr~echanism by which chromosome aberrations occur? marked homology to the heptamer-nonamer seThis question can best be answered by considering the quences (Table 1) found near immunoglobulin variable molecular characteristics of the chromosome trans- (3/), diversity (D) or joining (J) segments 4. l~.~:afions consistently found in B-cell and T-cell What is the significance of these features? They lymphomas and leukemiasx. bear directly on the mechanism of translocation when taken in the context of the physiological recombination Translocations associated with B-cell chronic which takes place at the Ig loci during B-lymphocyte lymphocytic l e u k e m i a and the involvement of ontogeuy4. The variable region of the immunogiobulin the immimog~obulin V-D--J recombinase heavy chain molecule is encoded by separate gene Malignancies of the B-lymphocyte lineage often segments, the Vx, D, andJa segments on chromosome exhibit chromosomal rearrangements that involve the 14. During the somatic development of the B cell, the cytogenetic locat{ons of the immunoglobulin (Ig) loci. segments are brought together in an orderly manner so Thus, chromosome band 14q32, the site of the lg that ultimately, in an immunogiobulin-producing B heavy chain locus, is often observed to be involved in lymphocyte, a contiguous Vn-D--Jx exon is formed. chromosome translocations. This feature of B-cell Recombination begins in most cases with D-JHjoining neoplasla has facilitated a molecular analysis of these on both alleles of a pre-B cell, followed by Vx to D-Ja translocations. Well-characterized molecular probes joining~. Once an lgH chain is expressed..'he light derived from the immunoglobulin loci were used to chains rearrange, first g, then ~., if necessarye. The enzymatic machinery through which this series demonstrate DNA rearrangements in these regions in various B-call tumors. Subsequently, genomic lib- of rearrm~ements is mediated is termed the raries were constructed from these malignancies, and recombinase4. The recombinase recognizes the molecular clones of the rearranged segments were heptamer-nonamer sequences found 3' of each Vx, on both sides of each D, and 5' of each Jx segment. The isolated and analysed. For example, some cases of chronic lymphocytic beptamer-nonamer comprises seven conserved nuleukemia (CLL) of the B-cell type exhibit a cleotides immediately abutting the respective segtranslocation between chromosomes 11 and 14, with ment, then a non-conserved spacer of 12 or 23 breakpoints at bands 11q13 and 14q32, the latter being nucleotides followed by a nine-nucleotide conserved the lg heavy chain locus (IgH). A silnilar translocation segment. Recombination may occur between a is observed in some cases of diffuse small cell and segment having a 12 base spacer (e.g. any DH diffuse large cell lymphomas. Probes from the joining segment) and a segment with a 23 base spacer (e.g. a segment of the heavy chain locus 0X) were used to JR segment). However, the molecular recombination isolate molecular clones containing the site of joining event is somewhat imprecise. At the site of joining, between chromosomes 11 and 14 in a case of CLLz, nucleotides may be deleted, substituted or added. and analysis of these clones demonstrated that the Additional nucleotides are called N regions; their breakpoint on chromosome 14 is found precisely presence correlates with the level of the enzyme withm the Js segment itself. At the nucleotide level, terminal deoxynucleotide transferase7. At the molecular level, the t(11; 14) breakpoints are the chromosome breakpoints show several interesting features3. (1) For two independent CLL cases, the thus very reminiscent of a physiologically recombining break occurs at the 5' end of the J4 segment (Fig. 1). immunoglobulin gene segment. Most importantly, the (2) The breakpoints are clustered on chromosome 11 breakpoints on chromosome 14 are clustered 5' of the as well; in fact, they lie within eight nucleotides of one Jti segments, precisely where one would expect to find another. The region of clustering on chromosome 11 breakage mediated by the recombinase (see Fig. 1). has been designated bcl-1 (B-cell leukemla/lymphoma- The regions of chromosome 11 surrounding the 1). (3) Around the breakpoint there are nucleotides breakpoints are notable for the presence of heptamerwhich, when compared with normal sequences from nonamer sequences (Table 1). Finally, N regions are 1987, Elsera~,~'~,~"~Pul~shersB V...amste.nlam 0 1 ~ - 9525/8~;I).200

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J6 97

, '.:~-J 3' SU-DHL-6/ \380t(8;14) FL 1144 FL 1003

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Fig. i. Clustering of chromosome breakpoints 5' OflHsegmeffte at the immunoglobulin heavy chain locus on chromosome 14. The close spacing of breakpoints at the nueleotide level strongly suggests that the recombinase is implicated in the mechanism of translocation in these various B-cell malignancies. Chromosome translocation occurs at or near the 5' end of eachJH segment, and downstream from the heptamer-nonamer signal sequences (indicated by 9 and 7). These are precisely the sites of ~hysiologitnl VH-D--]H jmning. Breakpoints designated FL, JLN w and S U-DHL--611 are from follicular lymphoma case~Jl ; CLL, chro~c lymphocytic leukemia'; 380 is an acute pre-B cell leukemia carrying t(8;14) and t(14;18) tra~locationsS; P3HR-1 is an African B urkitf s lymphoma (note that while the site of translocation in this tumor is upstream ofJS, a heptamer-~wnamer is situated at the break end nucleotides 3' of the breakpoint demonstrate some features of a pseudo-Ju segmentZ4).

present. The conclusion strongly suggested by these data is that the translocations in these CLL cases occurred through the mistaken operation of the immunoglobulin recombinase. Chromosome translocationsinvolving the V - D - J recombinase in other B-cell malignancies A molecular analysis of the translocation breakpoints of several other types of B-cell tumors has revealed that they share features with the t(11;14) of CLL. Specifically, follicular lymphoma (FL), acute lymphoblastic leukemia (ALL) and endemic Burkitt's lymphoma all show translocations involving this IgH locus. Cloned translocation breakpoints from each of these malignancies demonstrate characteristics implicating the recombinase in the pathogenesis of the translocation. The evidence is most convincing in the case of follicular lymphoma, which is the most common B-cell malignancy and in the majority of cases exhibits translocations involving chromosomes 14 and 18: t(14;18) (q32;q21). Using the strategy described above, and taking advantage of a cell line (380) carrying both t(14; 18) and t(8; 14) translocations, the FL breakpoint has been cloned; the region on chromosome 18 has been designated bcl-2 (Ref. 8). More than 60% of FL breakpoints are within a stretch of about 100 nucleotides in the 3' non-coding region of the bcl-2 gene9. Nucleotide sequence analysis of several FL breakpoints demonstrated features quite similar to those discussed above ~°. Chromosome 14 breakage occurred at the 5' end of the JH segments (Fig. 1) in accord with analyses of other t(14; 18) translocationsn'12. N regions were observed, and heptamer-nonamers were noted (Table 1). Note that in some cases only a heptamer has been found nearby the breakpoints. This is in agreement with findings at the K lOCUS13 and in VH to VH-D-JH recombination14. From the acute lymphoblastic leukemia cell line 380, which carries the t(14; 18) and t(8; 14) translncations, we also cloned the junction between chromosomes 8 and 14 (Ref. 8). Probes from this region of chromosome 8, which is situated more than 50 kh 5' of the c-myc oncogene (our unpublished results), detected the breakpoint of the endemic Burkitt's lymphoma P3HR-1, which also shows the t(8;14) translocation~s. Sequence analysis of these two t(8; 14) breakpoint clones again demonstrated breakage inJu, heptamer-nonamers, and N regions (Table 1 and Fig. 1). Thus, for all of these cases of B-cell

malignancy (including CLL, follicular lymphoma, ALL and endemic Burkitt's lymphoma) we can postulate that the chromosome translocation resulted from the aberrant functioning of the immunogiobulinVH-D-JH recombinase. Differences in the translocations in endemic and sporadic Burkitt's iymphomas Burkitt's lymphoma is a malignancy of the Blymphocyte lineage which can be classified into one of two formsTM. The first occurs endemically in equatorial Africa and is associated with the presence of Epstein-Barr virus (EBV) in more than 90% of cases, while the second occurs sporadically in Europe and North America, in the absence of viral infection. Endemic cases are rarely immunogiohulin secretors, whereas sporadic cases usually are. Burkitt's lymphomas of either type consistently exhibit one of three translocations. The majority of cases carry the t(8; 14), with a smaller proportion carrying t(2;8) or t(8;22). Each of these translocations juxtaposes the cmyc gene at band 8q24 with one of the immunogiobulin loci t. The t(8;14) translocations are themselves heterogeneous. If one analyses the DNA from tumors carrying t(8; 14) translocations by Southern blotting, using probes from the c-myc gene, one of two results is obtained1~. For a fraction of the tumors, DNA rearrangements can be demonstrated, indicating that the c-myc is structurally altered by the translocation. This is generally the result seen for sporadic Burkitt's lymphomas. Alternatively, no rearrangement can be found, as in most endemic, African Burkitt's Table I. Heptamer-nonamer sequences involved in B-ceU transiocations Chromosoffle

locauon 11q13 18q21

8q24

Celloforigin CLL1386 CLL271 FL 1032 FL 966 FL 1144 380 FL 1003 380 P3HR-I

Translocationconsensus 14q32

Sequence CTGACAG-12-ACAAAGCCT TACGCTC-12-AGGAAACCT CAGAATG CGCCTTT-12-TTAAAAATT CGCGGGG CTCTGAG CCCTTTG-12-TAAATCTTG CNCNNTG-12-~AAAAC~T

lgH consensus~ CACAGTG-12-ACAAAAACC

"ConsensusforhumanDsegments3~.

review

TIC, [ 3 ] - January 1987

Table 2. Comparison of features of endemic and sporadic Burkitf s lymphomas Geographiclocation EBVpresence lg.Msecretor c-mycrearranged Recombinase-mediated translocation Isotype switch-mediated translocation

Endemic EquatorialAfrica +

Sporadic Europeand NorthAmerica -

+

that the sporadic Burkitt's lymphoma derives from a B lymphocyte at a more differentiated stage of ontogeny, and that mistakes in isotype switching give rise to the ~anslocations in these tumors. Figure 2 illustrates the differences one observes at the molecular level in the endemic and sporadic Burkitt's iymphomas.

-

+

+

-

The relationship of translocation mechanism to B - l y m p h o c y t e ontogeny

-

+

From the above discussion, it is clear that the type of molecular mechanism that results in a B-cell translocation is a function of the stage of differentiation of the affected cell. As a corollary, knowing the molecular structure of a translocation, we can deduce the cell of origin for a given tumor. These points are illustrated in Fig. 3. Yet, despite our ability to draw conclusions about the enzymatic mechanisms underlying these translocations, there remain several unanswered questions regarding cellular control of these events. Most importantly, it is not clear how the activity of the putative recombinase is controlled. The enzyme clearly recognizes the defined signal sequences described above. But these sequences occur many times throughout the Ig loci, and presumably are randomly distributed throughout the genome as well. Why, then, do we not observe random translocafions? One reason is that in the malignancies already considered, the translocation has imparted a clonal proliferative advantage to cells carrying it by juxtaposing c/s-activating sequences (the IgH locus enhancers) and genes having a role in cellular growth control (c-myc, bcl-1 and bcl-2). Thus, the presence of the non-random translocation is selected for. Indeed, the translocation is at the very root of oncognnesis. In addition, it has been demonstrated that the accessibility of regions to recombinase function correlates

lymphomas. Thus, in terms of their epidemiology, their status of EBV infection, their immunology and their molecular biology, endemic and sporadic Burkitt's iymphomas differ (Table 2). Does this reflect different mechanisms of translocation as well? It does, in that most endemic Burkitt's lymphomas probably employ the VH-D-JH mechanism, while the sporadic cases may result from mistakes in isotype switching. The endemic Burkitt's lymphomas are exemplified by P3HR-1, the breakpoint of which is described above. Another example is the Mrican Burkitt's lymphonm cell line Daudi, the breakpoint of which involves the Vn segments, and which may also have resulted from a Vn-D-JH joining mistake is. Aberrant use of the recombinase at an early stage of B-cell differentiation is in accord with the nonsecretor status of most African Burkitt's iympbomas. In contrast, we have also doned the breakpoint of a sporadic Burkitt's tumor ~. The breakpoint involves the first intron of c-myc on chromosome 8, where switch-like sequences are found, and the Cffiswitch region on chromosome 14. The C~ switch region has also been demonstrated to be the site of breakage in other sporadic Burldtt's lymphomas2°. This suggests

14q32 Co

14q32

S~ II c - m y c III

8q24

8q24 "-myc

Fig. 2. Differences in the t(8;14) chromosome translocalion between the African Burkitf s lymphoma P3HR-1 (R ef. 14) and the sporadic Burkilf s lymphoma CA 46 (Ref. 18). The 14q+ chromosm~e is illustrated for each. In P3HR-I, the breakpoint lies upstream of]5 on chromosome 14, and greater than 50 kb 5' of the intact c-myc on chromosome 8. The recombinase may have mediated this translacation. In contrast, the CA 46 translocation j~n~ chromosome 14 switch sequences with the intron s@arating the first (I) and second (II) exons of c-myc. This may have occurred through the action of iso(ype switching enzymes.

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TIG [3] ~ Janumy 1987 Pre-B cell

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Fig. 3. Correlation between B-lymphocyte ontogeny and the point at which translocah'ons leading to malignancy occur. The recombinasefunctions in pre-B cells or immature B cells. At these stages of differentiation, its physiologicalfundion is to implement Vw-D-JH joining, VH to Vw-D-]H recombination, or VL-JL joining. Errors at these steps may give rise to translocations, as observed in follicular lymphomu, chronic lymphocyticleukemia, acute lymphoblastic leukemia and endemic Burkitt"s lymphoma. In more mature cells, isob,peswztching tahes place foUowing antigenic stimulation. Thus, in mature B cells, transiocations of the type seen in sporadic Burkitt" s lymphomas may occur.

with chromatin configuration and transcriptional has also been described in a B-cell ALL, and it too activity2z. Thus, regions in an accessible chromatin juxtaposes an Ig VHwith a TCRJ ¢ segment~. In both configuration, and transcribed regions, are susceptible instances, the recombinase has evidently functioned to translocation. It is important to realize that these two abnormally to join segments from these two different factors can vary independently. Chromatin configura- loci. Taken together, all of these findings strongly tion studies on the expressed, translocatedc-mycallele support the hypothesis that the recombinase causes Band the normal, silent allele in Burkitt's lymphoma have and T-lymphocyte translocations. shown that both copies ofc-myc display sinfilar DNase I hypersensitivity patterns, despite their different An overview: scenarios leading to chromosome transcriptional states z2. However, the silent c-myc translocationandneoplasia gene in K562 erythroleukemia cells has no hypersensiThe discussion so far has mainly dealt with the issue tivity to DNase I digestion23. The chromatin configur- of defining the molecular mechanisms responsible for ation of c-myc in the Burkitt's lymphoma cells translocations in lymphoid malignancies. It has apparently is modulated apart from transcriptional emphasized the realization that cytogenetic abneractivity, in a differentiation-specificfashion, and in fact realities can result from the operation of the enzymes may facilitate the observed translocations. which catalyse physiological recombination in specific differentiation backgrounds. B- and T-lymphocytes T-celltranslocations use these enzymes to maximize the diversity of their The T-cell o~chain genes are located at chromosome respective antigen-recognition repertoires. Yet some band 14ql 1, and at the molecular level are organized in proportion of the time, the enzymes malfunction and much the same way as the IgH locus. Thus, it is not give rise to cancer. surprising that this site is the most frequently Under what circumstances does this occur? We can observed location of cytogenetic abnormalities in T- best answer this question for the case of Burldtt's cell malignancies 24. It has been demonstrated recently lymphoma. As discussed earfier, African Burkitt's that the recombinase which mediates immunoglobulin lymphomas are notable for their association with the recombination functions to rearrange T-cell receptor presence of EBV. At one time, it was thought by many (TCR) gene segments as well21. Is this enzymatic investigators that EBV might be the etiological agent machinery implicated in T-cell translocations? of this tumor. Recently, it has become evident that the A T-cell line carrying a t(8;14) (q24;q11) transloca- crucial step toward neoplasia is the activation of the ction was used to investigate this question~. The myc gene by translocation; so what is the significance demonstration that c-myc is involved in this trans- of the EBV association? Our current view of the location, in much the same way as in B-cell neoplasia, answer to this question is summarized in Table 3 (also facilitated the molecular cloning of the breakpoint. In see Refs 16 and 28). EBV is a polyclonal activator of Bthis tumor, however, aJ o~segment from chromosome lymphocytes, and infection of normal B cells/n v/tro by 14 is fused 3' of the c-myc third exon. As in the EBV is associated with immortalization. In regions of B-lymphocyte cases, heptamer-nonamers and N equatorial Africa where Burkitt's lymphoma is regions are found, and so one can conclude that the endemic, more than S0% of children demonstrate aberrant function of the recomhinase gave rise to this evidence of EBV infection. This region is also one of translocation. hyperendemic malaria. The hypothetical scenario that Studies on the inv14 (ql I; q32) paracentric chromo- presents itself is as follows. Infection of a young some inversion support the contention that the individual in this area by EBV occurs without clinical recombinase is also operative in other T-cell translo- disease. However, if the individual contracts malaria, cations. It has recently been shown that in a T cell, this immunosuppression ensues. Polyclonal B-lymphocyte inversion results from the site-specific recombination proliferation proceeds unchecked in the absence of Tof an Ig VH segment, from band 14(132, with a TCRJ o~ cell suppression, probably enlarging the population of segment, at band 14q11 (Ref. 26). A similar inversion cells susceptible to another genetic change such as

TIC, [3] - - ] a ~ m ~

review

1987

Table 3. Possible scenarios for chromosome tra~location in

tymp~oidmaUenaeW.s Expansionof lymphoid compartment EBVinfection

manuscript, and Ms Charlotte Long for preparation of the manuscript. F. Haluska is a trainee of the Medical Scientist Training Program at the University of Pennsylvania School of Medicine, NIH 1"32 GM 07170.

lmmunosuppressive Resultingtranslocation event and malignancy H~-~erendemicmalarin t(8;14)EndemicBmddtt's R e f e r e n c e s lymphoma / Croc~, C. M. and Howe", P. C. (1986) Adv. lmmunol. 38, EBVinfection HIV refection with t(8;14)BurkJtt's-like 245-274 AIDS lymphoma 2 Tsujimoto, Y. et aL(1984)Science 224, 1403-1406 HTLV-linfection None Abnormalband 14(111 3 Tsujimoto, Y. et al. (1985)NaCre 315, 340-343 ATL 4 Tone~wa, S. (1983)Nature 302, 575-581 5 Ait, F. W. et aL (1984) EMBO ]. 3, 1209-1219 6 AI4 F. W., Enea, V., Bothwell, A. L. M. and Baltimore, D. translocation. Ultimately, a translocation occurs (1980) Cell 21, 1-12 involving the IgH locus and leading to deregulation of 7 Desiderio, S. V. et al. (1984)Nature 311, 752-755 the c-myc oncogene; aggressive malignant lymphoma 8 Tsujimoto, Y. el o1. (1984)Sc/ence226, 1097-1099 9 Tsujimoto,Y., Grossman,J., J~fe, E. and Croce, C. M. (1985) results. 228, 1440-1443 In Europe and North America, childhood EBV 10 Selene Tssj~noto, Y. etal. (1985)Sc/e~ 229, 1390-1393 infection is less frequent, as is malaria. Thus, the l l Clem'y,M. L. and Sklar, J. (1985)Prec. NatlAcad. Sd. USA sporadic form of Burkitt's lymphoma occurs with a 82, 7439-7443 dramatically reduced incidence, probably in mature B 12 Bakhshl, A. et al. (1985)Cell 41, 899-906 cells, following antigenic stimulation and during 13 Seidman,J. G. and Leder, P. (1980)Nature 286, 779-783 14 Kleinfield, R. el al. (1986)Nalure322, 843-846 isotype switching. However, in one patient popuh- 15 Halualm, F. G., Finver, S., Tsujimoto, Y. and Croce, C. M. tion, a form of lymphoma designated Burkitt's-like N a ~ Cmpress) iymphoma (BLL) has been described. Patients with 16 Klein, G. and Klein, E. (1985)Nature 315, 190-195 AIDS often develop this tumor ~. In this case, 17 Pelicci, P-G., Knowies, D. M., II, Ma~'ath, L and DallaFavem, R. (1986)Proc. Nati Aead. SoL USA 83, 2984-2988 infection by the human immunodeficiency virus (HIV) 18 Er~son, J., Finan,J., Nowell,P. C. and Grote, C. M. (1982) engenders immunosuppression. EBV infection folProc. Nag Acad. $ci. USA 79, 5011-5015 lows, and translocations similar to those seen in the 19 Showe, L. C. et aL (1985)Mol. Cell. Biol. 5, 501-509 African Burkitt's lymphomas occur. The important 20 Gelmann: E. P., Pssll~lopoulos, M.C., Papas, T.S. and Dalh-Favera, R. (1983)Nature 306, 799-803 point here is that an expanded B-lymphocyte 21 Yancopoulos,G. D. el aL (1986)Celt 44, 251-259 compartment is likely to enhance the probability of 22 Siebenlist, U., Henedghanssn, L., Battey, J. and Leder, P. tTanslocation, and this expansion occurs when T-cell (1984) Cdi 37, 381-391 23 Tuan, D. and London,L M. (1984)Proc. Natl Acad. SoL USA suppression is abated. 81, 2718-2722 A similar mechanism may operate in T-cell 24 Croce, C. M. et al. (1985)Science 227, 1044-1047 malignancy. Adult T-cell leukemia (ATL) is associated 25 Finger, I, R. et aL S c i e ~ (m pre~) with HTLV-I infection, and it is thought that the virus 26 Bast, R., Chen, K-C., Smith, S. D. and Rabbitts, T. H. (1985) is in fact the etiological agent of this cancer. However, Cell 43, 705-713 these tumors can consistently be shown to carry 27 Denny, C. T. et aL (1986) Science234, 197-200 giegier, J. L. (1981).IV.E~.q. ]. Med. 305, 735-745 cytogenetic abnormalities at band 14q11, the site of 28 29 Ziegler, J. L. et al. (1982)Lancet fi, 631-633 TCR o~ (Ref. 30). Since HTLV-I infection results 30 Sadamori, N. et aL (1985) Cancer GeaeL Cyto&enet. 17, in increased IL-2 production and T-lymphocyte 279-282 stimulation, the virus may function to enlarge the 31 Siebenl~st,U. et al. (1981)Nature 294, 631-635 population of cells susceptible to translocation, in much the same manner as described for B cells. F. G. H a l ~ k a , Y. Tsujimoto and C. M. Croce are at the The underlying unity observed in the mechanisms Wistar Institute of A~mtomy and BioloRy, 36th and S p ~ c e by which chromosome aberrations arise in B and T Streets, PMtaddphia, P A 19104, USA. cells is striking. However, much remains to be learned about mechanisms of chromosome translocation in non-lymphoid malignancies. For instance, the process which gives rise to the Philadelphia chromosome m myeloid leukemia is not understood at present, despite the fact that much is Imown about the molecular nature of the t(9;22) translocation. Yet, given that all tumors exhibit chromosome abnorFor free publicity about your course, malities, we can predict that eventually a straightworkshop, symposium etc, send details forward appfication of these types of analyses will be to Trends in Genetics, 68 Hills Road, made to most tumors. Elucidation of these mechanisms will provide us with key insights into the Cambridge CB2 1LA, UK. pathways by which malignancies occur. At that point, For information on paid advertising we will be able to begin a rational approach to the molecular diagnosis and therapy of malignancy. contact Louise Morse at the same

Genetic Jottings

Acknowledgements We would like to thank Dr Paul Shaman for useful comments, Dr Masaharu lsobe for reviewing the

address: phone (0223) 315961: Telex 81623: Fax (0223) 321410.