Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia

10TH ANNIVERSARY ARTICLE Inversions and Tandem Translocations Involving Chromosome 14qll and 14q32 in T-Prolymphocytic Leukemia and T-Cell Leukemias in Patients with Ataxia Telangiectasia V. Brito-Babapulle and D. Catovsky

ABSTRACT: Ataxia telangiectasia (AT) and T-prolymphocytic leukemia (T-PLL) have similar chromosome abnormalities. Cytogenetic findings reported in 5 patients with AT who developed T-cell leukemia revealed: inv(14)(qllq32) (1 case), tandem translocations of chromosome 14 with breakpoints at ql I and q32 (3 cases), and int. del(14 )(q l lq32) (1 case). Additional abnormalities were present in 4 patients of whom two had trisomy for 8q. 0 f 2 7 patients with T-PLL but without AT, investigated by us, 17 had inv(14 )(q1 lq32) and 3 had tandem rearrangement of chromosome 14 with breaks at 14qll and q32; 15 of them also had rearrangements resulting in trisomy 8q. Two of the leukemias supervening on AT had morphology and clinical course suggestive o] T-PLL. Two other cases of A T studied by us developed typical T-PLL at a young age (18 and 39 years). T-cell clones carrying an inv(14), tandem t(14;14) and t(X;14) can be present in A T for long periods of time without evolving into leukemia. In T-PLL, inv(14) and t(14;14) always occurs with other chromosome abnormalities. We suggest that these additional chromosome abnormalities may be required for the leukemic transformation of AT. This is supported by one of the two AT cases studied by us in which a long-standing t(X;14) clone evolved with the formation of t(1;14)(p21;ql 1), t(8;22)(q24;ql 1) at the time of the development of T-PLL.

INTRODUCTION The close a s s o c i a t i o n b e t w e e n p a r t i c u l a r c h r o m o s o m e a b n o r m a l i t i e s and certain t y p e s of m a l i g n a n c y i n d i c a t e s that s u c h a b n o r m a l i t i e s m a y h a v e a c a u s a t i v e role in the c a n c e r process. In l y m p h o i d n e o p l a s m s t r a n s l o c a t i o n s b e t w e e n sites of f u n c t i o n a l l y significant genes s u c h as the i m m u n o g l o b u l i n genes (Ig) in B cells and the T-cell r e c e p t o r genes (TCR) in T-cells and sites of o n c o g e n e s are c o m m o n [1-3]. T h e TCR a and 3 c h a i n genes h a v e b e e n m a p p e d to 1 4 q l l [4, 5], the fl c h a i n g e n e to 7 q 3 5 - 3 6 [6], 3' c h a i n gene to 7p14 [7], w h i l e the Ig h e a v y (H) c h a i n gene has b e e n m a p p e d to 14q32 [8]. In T - l y m p h o b l a s t i c l e u k e m i a , b e c a u s e of the p r e s e n c e of a c t i v e l y d i v i d i n g blasts in the p e r i p h e r a l b l o o d and b o n e m a r r o w , s p o n t a n e o u s mitoses m a y be o b t a i n e d for From the Academic Department of Haematology and Cytogenetics, Royal Marsden Hospital, and Institute of Cancer Research, London, U.K. Address reprint requests to: Dr. V. Brito-Babapulle, Academic Department of Haematolagy & Cytogenetics, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, U.K. Received January 18, 1991; accepted January 18, 1991.

1 © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas~ New York, NY 10010

Cancer Genet Cytogenet 55:1-9 (1991) 0165-4608/91/$03.50

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V. Brito-Babapulle and D. Catovsky study without the use of mitogens. However. in malignancies resulting from the proliferation of T-cells with a mature post-thymic membrane phenotype ( T d T - , CDla - ,CD2 + ,CD3 + ), mitoses can be obtained with the use of T-cell mitogens such as phytohemagglutinin (PHA), concanavalin-A (Con A), 12-O-tetradecanoyl phorbol13-acetate (TPA) alone or in combination with purified T-cell growth factor or interleukin 2 (IL-2) or conditioned medium containing IL-2 from cultures of normal T-cells stimulated by PHA. We have been interested in two abnormalities of chromosome 14 where there is juxtaposition of 1 4 q l l with 14q32, namely inv(14){qllq32) and tandem translocation t(14;14)(q11;q32). These two abnormalities have been described most frequently in T-cell leukemias in patients with ataxia telangiectasia (AT) and in T-prolymphocytic leukemia {T-PLL) [9, 10]. Their incidence in other T-cell malignancies appears to be lout [10], although, in a recent report on peripheral T-cell lymphoma, three of seven cases had inv(14)(qllq32) [11]. In a previous literature survey, only 1 of 40 cases of peripheral T-cell lymphoma had inv(14) [10].

Ataxia Telangiectasia (AT) AT is an autosomal recessive syndrome characterized by cerebellar ataxia, oculocutaneous telangiactasia, varying degrees of immune deficiency, and an increased incidence of malignancy. A high percentage of these neoplasms are lymphoid and predominantly of T-cell origin [12-14]. Cytogenetic analysis of lymphocytes from AT patients shows an increased incidence of chromosomal rearrangements involving bands 7p13-14, 7q32-35, and 14q11, which are sites of the TCR genes, and 14q32, to which the IgH gene is mapped [15-17]. These abnormalities may be sporadic or clonal. In a series of 72 patients with AT, 11 clones were observed, of which 6 clones were inv(14)(qllq32) [18, 19]. In another study of 40 patients with AT, most showed the presence of small T-cell clones. Three patients had large clones consisting of inv(14)(qllq32) (100% of ceils), t(14;14)(q11;q32) (70% of cells), and t(X;14)(q28;q11) (80% of cells). All these large clones were CD3 + ,CD8 +, CD4 - [20]. Sporadic inv(14) have been observed in about 15% of normal B and T lymphocytes, probably resulting from errors in TCR IgH rearrangements [21]. Interestingly, the inv(14) and t{14;14) in AT appears to be associated with a slowly increasing T-cell population, which can occasionally undergo malignant transformation [22, 23], whereas the frequency of sporadic inv(14) in normal individuals tends to decrease with the age of the control subjects [19]. A cyt0genetic study of elongated chromosomes revealed that the breakpoint on 14q32 in sporadic inversion 14 is q32.3 while in AT clones it is q32.1 [18]. Furthermore, AT clones were shown to share a c o m m o n breakpoint 14q11.2, which splits the T cell receptor c~ chain gene [24].

T-Prolymphocytic Leukemia The two abnormalities of AT, inv(14) and t(14;14), were of interest to us when we started investigating the chromosome abnormalities in prolymphocytic leukemia (PLL). PLL was originally described by Galton et al. [25]. Twenty percent of cases have a T membrane phenotype and 70% correspond to classic B-PLL. Clinically, TPLL cases have splenomegaly (72%), hepatomegaly (42%), lymphadenopathy (55%), and present with a high WBC count (median 230 x 109/L; range 28-1000). Some patients have skin lesions but not erythroderma and the lesions do not involve the epidermis, as in S~zary syndrome [26, 27]. Prolymphocytes are medium-sized cells with a single prominent nucleolus and T-prolymphocytes can be distinguished from B-prolymphocytes by their smaller size and marked cytoplasmic basophilia. In 25%

3

1 4 q l l and 14q32 in T-PLL and AT

Table 1

Specific Chromosome Abnormalities in T-PLL without AT (27 Cases)

inv(14)(qllq32/ t(14;14)(q11;q32) der(10)t(10;14;14)(p11;qllq32;q11) der(11)t(11;14;14:(p11;qllq32;q11) i(8q) t(8;8)(p12;q11) + t(8:21)(p12;q11) + t(2:8)(q21;q11) +8p+

1 1/

/

3--

20 (74%)

9

of T-PLL cells the nucleolus is not readily visible in Romanovsky-stained preparations, but is always recognized by ultrastructural analysis [26, 27]. Furthermore, the nucleus of a T - p r o l y m p h o c y t e can often be irregular in shape and may sometimes present problems of differential diagnosis with adult T-cell l y m p h o m a / l e u k e m i a and Sezary cells. Membrane markers show that 67% of cases are C D 4 + , C D 8 - , 18% CD4 + , CD8 + , 11% C D 4 - , CD8 + , and 3% C D 4 - , C D 8 - . T-PLL is a very aggressive disease and the m e d i a n survival of the first 40 patients investigated in our unit was 7 months [26, 27]. Of 27 T-PLL patients studied by us, 17 had inv(14)(qllq32) and three had t a n d e m arrangement of 14, t(14;14)(q11;q32) (Table 1 and Figs. 1 and 2). Three patients had abnormalities involving 7q33-35, the region to w h i c h the TCR /3 chain gene is mapped. No patient had abnormalities of 7q33-35 (TCR /3 chain region) and rearrangements of 1 4 q l l (TCR a chain region) occurring simultaneously. On the other hand, both these abnormalities of chromosome 7 and 14 coexisted with several other abnormalities. In 15 cases rearrangement resulting in trisomy for 8q was observed. Of these, 13 were present together with inv(14) or t(14;14), while two were present with a c h r o m o s o m e 7q33-35 abnormality. In preneoplastic AT clones, abnormalities of c h r o m o s o m e 7 do not appear to have m u c h proliferative advantage w h e n c o m p a r e d to clones with inv(14) and t(14;14) [20]. However, the different proliferative kinetics between small clones with c h r o m o s o m e 7 abnormalities and large clones with chromosome 14 abnormalities is not seen in T-PLL where the a d d i t i o n a l abnormalities, chiefly trisomy for 8q, may override this difference. The role of trisomy for 8q is further s u p p o r t e d by two patients with AT and T-cell leukemia in w h o m i(8q) was a secondary abnormality. Unlike in AT, where preneoplastic clones with inv(14) or t(14;14) are present as primary abnormalities, clonal evolution in T-PLL is difficult to determine due to the simultaneous presence of several chromosome abnormalities. However, in one of the 27 patients in our study trisomy for 8q due to a + t(8;8)(p12;q11) and t(11;12)(q21;q24) were present in all 50 cells analyzed, while inv(14)(qllq32) was present only in 10% of the cells. Thus, in this case inv(14) was not the primary abnormality. In all the other cases where the inv(14) and t(14;14) were present, they occurred in all the karyotypically abnormal cells. T-Cell Leukemia in Ataxia Telangiectasia (Table 2) The study of a T-cell clone from a 13-year-old boy with AT revealed that the clone was confined to CD4 +,CD8 + and C D 4 - , C D 8 + cells and was characterized by a t(14;14) [28]. The WBC was 8.9 x 109/L and 70% of metaphases had the translocation. L y m p h o c y t e s with p r o l y m p h o c y t e m o r p h o l o g y were demonstrated in the p e r i p h e r a l blood [28]. Patients numbers 3 and 7 in Table 2 who had AT and T-cell leukemia also

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v. Brito-Babapulle and D. Catovsky

II

14

Case 12 Figure 1

t(11;14)(p13;qllq32;q11) in a patient with T-PLL.

had cells resembling prolymphocytes and they both had an acute clinical course like T-PLL. Furthermore, two patients with AT and CD8 + T-PLL were diagnosed in our laboratory (patients nos. 6 and 8, Table 2). Of the seven cases of mature T-cell leukemia supervening AT (case nos. 1 - 4 and 6-8) in Table 2, four were CD8 +, two were CD4 + ,CD8 + and only one was CD4 +, while of the 27 patients with T-PLL w i t h o u t AT w h o m we investigated, four were CD8 +, six were CD4 + ,CD8 + , and 17 were Figure 2

inv(14)(qllq32) and 3 copies of i(8q) in a patient with T-PLL.

case

8

1 4 q l l a n d 14q32 i n T-PLL a n d A T

Table 2

T Leukemias in Ataxia Telangiectasia

Patient

Chromosome abnormalities

1 AT5-B1

inv(14); inv(14), 1 1 p - ; inv(14) 11p , i(8q), 6 q - , etc.

2

t(14;14)

3

t(14;14), t(13;15), t(13;17), 18q+

4

t(14;14), +14, 12, 6q-, 12p-, 20p+, i(8q)

5 6~ 7

8 ~'

Complex clonal abnormalities including int del(14)(q21q32). t(X;14)(q28;q11) t(1;14/(p21;q11) Other abnormalities including t(8;22) (q24;q11).

5

Clinical details

(Refs)

29-year-old woman. Chromosomally abnormal, stable but evolving clone was present for 5 years. The patient then developed T-cell leukemia with generalized lymphadenopathy, hepatomegaly & splenomegaly. WBC 700 x 10~/L. 97% of CD3 +, CD8 + T-lymphocytes. 38-year-old woman. Had preneoplastic clone for over 10 years. For the last 3 years the WBC was stable at 35 x 10~/L, 60% mature T-lymphocytes with a CD3 +, CD4 + phenotype. Diagnosed as chronic T-cell leukemia. Older sister of patient 2. Examination at the age of 25 revealed WBC 48.4 × 10"/L with 73% T-lymphocytes with prominent nucleoli resembling prolymphocytes. No organomegaly but acute clinical course. 48-year-old woman with elevated WBC 66 x 10'J/L. No organomegaly. T-lymphocytes with CD4 +, CD8 + phenotype diagnosed as chronic T-cell leukemia. 10 years prior to developing leukemia 100% of PHA stimulated ceils had t(14;14). 12-year-old male, diagnosed as having T-ALL. 18-year-old male with classical T-PLL. 29-year-old male with WBC 80 x 10~/L. Cells medium sized, prominent nucleolus. CD4 + ,CD8 +. No organomegaly. Acute clinical course. 20-year-old woman who had a premalignant CD8 + clone with a t(X;14)(q28;q11). Classical T-PLL in same clone with additional abnormalities. Acute clinical course.

[22, 30]

[31, 33]

[33]

[23, 32, 34, 35]

[42] [43]

[20]

° Morphology and phenotype studied by Dr. M. P. de Oliveira; no chromosome data available. ~'T-PLL diagnosed and cytogenetics on leukemic cells done in our laboratory.

CD4 + . T h e CD4 + ,CD8 + m e m b r a n e p h e n o t y p e o c c u r s i n a b o u t 2 0 % of T-PLL, b u t it is v e r y rare in o t h e r m a t u r e T-cell l e u k e m i a s .

Molecular Genetics of inv(14)(qllq32) and t(14114)(q11;q32) In 1986 a s t u d y w a s p e r f o r m e d o n a ceil line, S U P - T 1 , d e r i v e d f r o m a c h i l d h o o d Tcell l y m p h o m a w i t h a n i n v ( 1 4 ) ( q l l q 3 2 ) [29]. T h e s t u d y r e v e a l e d t h a t t h i s p a r t i c u l a r inversion was mediated by a site-specific recombination event between an immunog l o b u l i n h e a v y - c h a i n v a r i a b l e r e g i o n o n 14q32 a n d a T-cell r e c e p t o r c h a i n j o i n i n g s e g m e n t (TCR Jc~) o n 14q11. T h e h y b r i d g e n e w a s t r a n s c r i b e d i n t o p o l y ( A ) + RNA. H o w e v e r , it is d i f f i c u l t to e n v i s a g e t h e s e l e c t i v e a d v a n t a g e s u c h a t r a n s l o c a t i o n c o u l d c o n f e r o n t h e cell, as it d i d n o t i n v o l v e a n o n c o g e n e . S i n c e t h e n , m o l e c u l a r a n a l y s i s of a n i n v ( 1 4 ) i n a large A T c l o n e w h i c h d e v e l o p e d i n t o l e u k e m i a (AT5-B1) [30] a n d

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V. Brito-Babapulle and D. Catovsky

three patients with AT who developed chronic T-cell leukemia [31, 32] and carrying a t a n d e m t(14;14)(q11;q32) have been reported (Table 2). Molecular analyses of one non-malignant T-cell clone in an AT patient with the t(14;14) [36], three patients with T-cell leukemia without AT, one diagnosed as having T-CLL and carrying an inv(14)(qllq32) [37, 38] and designated LinV, another patient who had T-PLL and a t(14;14)(q11;q32) designated Pt [37], and the third patient who had a T-cell acute lymphoblastic leukemia carrying a t(14;14)(q11;q32) [39, 40], have been reported. In all eight reported cases, although the breakpoint on 1 4 q l l was within the TCR Jc~ locus, the breakpoint on 14q32 was centromeric to the IgH locus (14q32.3) and m a p p e d to 14q32.1. Molecular characterization using in situ hybridization of an inv[14} in an AT T-cell clone showed that the breakpoint on 14q32 differed from the breakpoint in inv(14) in the cell line SUP-T1, which involved the IgH gene [19, 28]. These findings demonstrate that there are two kinds of breakpoints on 14q32, one associated with sporadic inversion 14 with no proliferative advantage and those in AT clones and T-leukemias (chiefly T-PLL) in non-AT patients where the breakpoint is on 14q32.1. In the cell line SUP-T1, where the inv(14) breakpoint on 14q32 is comparable to the sporadic inv(14), this particular abnormality probably did not contribute to lymphomagenesis, but other chromosome abnormalities which were pathogenic could have arisen in a cell which had a sporadic inv(14). However, a coding region for a cellular transforming gene has not yet been identified in 14q32.1. Although a close molecular link (2.1 kb) has been demonstrated between inv(14) breakpoints in AT5B1 and LinV [41], suggesting that the pathogenesis of chronic T-cell l e u k e m i a in AT and non-AT patients may be similar, comparison of restriction maps and sequence data from other reported cases fails to indicate that a breakpoint cluster is present. Unlike follicular l y m p h o m a , where there is a major breakpoint cluster w i t h i n 4.3 kb on chromosome 18q21 [44], it appears that breakpoints on 14q32 can occur over a relatively broad range centromeric to IgH gene in T-cell leukemias. This lack of tight clustering of the breakpoint may be analogous to the situation in some Burkitt l y m p h o m a s where, although levels of c-myc mRNA are comparable in tumors bearing the variant and standard translocations, the chromosome breakpoints in the variant translocation t(2;8) generally do not occur near c-myc but instead fall a substantial distance, usually unknown, 3' of the gene, with some breakpoints as far as 260 kb from the myc gene [45]. The h u m a n homologue of the retroviral oncogene AKT-1, which was originally derived from the murine thymus, has been localized to 14q32 to a region centromeric to the IgH locus [46], but as yet there is no evidence that this gene is involved in the t(14;14) and inv(14). CONCLUSION Although an oncogenic sequence has not been identified, and there is no definite clustering of breakpoints on 14q32.1, T-cells bearing t(14;14)(q11;q32) and inv(14)(qllq32), where the breakpoint is centromeric to the IgH locus, have a proliferative advantage in AT patients [20]. Apart from the above two rearrangements, translocations between chromosomes 14 and X have also been associated with large clones [20, 47]. It is possible that patients with T-PLL had preneoplastic clones with inv(14) or t(14;14) before developing overt leukemia but are not, as a rule, investigated before the d e v e l o p m e n t of leukemia, while AT patients are usually routinely investigated for chromosomal clones. Since preneoplastic T-cell clones carrying an inv(14), t a n d e m t(14;14), and t(X;14) can be present in patients in AT for long periods of time, their primary function is possibly one of activation. This is confirmed by the report on a patient with AT with t(14;14) in a preneoplastic clone, w h i c h had l y m p h o c y t e s with p r o l y m p h o c y t e morphology [28]. In T-PLL, inv(14) and t(14;14) always occur together

1 4 q l l a n d 14q32 in T-PLL and A T

7

w i t h o t h e r c h r o m o s o m a l a b n o r m a l i t i e s . We postulate, therefore, that t h e s e a d d i t i o n a l c h r o m o s o m a l a b n o r m a l i t i e s m a y be r e q u i r e d for the d e v e l o p m e n t of overt and progressive l e u k e m i a in b o t h A T and T-PLL in the a b s e n c e of AT. O n e p a t i e n t w i t h A T had a t(14;14) c l o n e for o v e r 10 years and in the last 3 years d e v e l o p e d c h r o n i c T-cell l e u k e m i a w i t h a WBC w h i c h was stable at 35 x 109/L w i t h 60% CD4 + m a t u r e l y m p h o c y t e s [31]. A l t h o u g h a d d i t i o n a l a b n o r m a l i t i e s i n v o l v i n g o t h e r c h r o m o s o m e s w e r e not present, a 17 kb i n t e r n a l d e l e t i o n 3' to the t r a n s l o c a t i o n was o b s e r v e d [31]. A n A T gene has b e e n l o c a l i z e d to c h r o m o s o m e 1 1 q 2 2 - 2 3 [47] but as yet, there is no clear e v i d e n c e of h o w this p r e d i s p o s e s to m a l i g n a n c y . At least w i t h the l y m p h o i d n e o p l a s m s , the p a t h w a y m i g h t be t h r o u g h i m m u n e d e f i c i e n c y and c h r o m o s o m e instability. F u r t h e r studies are r e q u i r e d to e l u c i d a t e the m e c h a n i s m of p a t h o g e n e s i s of these l e u k e m i a s . It is, n e v e r t h e l e s s , striking that the s a m e a b n o r m a l i t i e s are s e e n in t w o d i s o r d e r s r e s u l t i n g in p r e m a l i g n a n t and overtly m a l i g n a n t T-cell clones, often w i t h the m o r p h o l o g y of p r o l y m p h o c y t e s .

This work was supported in part by a grant from the Medical Research Council. We are indebted to Alison Crawford and Jane Ellis for assistance with karyotype analysis and Drs. E. Matutes and M. P. de Oliveira for advice and clinical information.

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V. B r i t o - B a b a p u l l e a n d D. C a t o v s k y

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