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T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children a
b
b
Raul C. Ribeiro , Susana C. Raimondi , Frederick G. Behm & Ching-Hon Pui
ab
a
Departments of Hematology-Oncology St. Jude Children's Research Hospital, and the Departments of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee, USA b
Departments of Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, and the Departments of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee, USA Published online: 01 Jun 2015.
To cite this article: Raul C. Ribeiro, Susana C. Raimondi, Frederick G. Behm & Ching-Hon Pui (1992) T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children, Leukemia & Lymphoma, 7:5-6, 351-358 To link to this article: http://dx.doi.org/10.3109/10428199209049790
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Leukemia and Lymphoma, Vol. 7, pp. 351-358 Reprints available directly from the publisher Photocopying permitted by license only
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T-cell Acute Lymphoblastic Leukemia with t(11;14) in Children RAUL C. RIBEIRO,' SUSANA C. RAIMONDI,' FREDERICK G. BEHM,2 and CHING-HON PUI'v2
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'Departments of Hematology-Oncology, 2Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, and the Departments of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee, U.S.A. (Received 25 February 1992)
We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(1 1;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(ll;l4), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t( 11;14)(p13;qll) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance. KEY WORDS:
T- ALL
t(l1;14)
Pediatric ALL
INTRODUCTION Chromosomal translocations are common findings in childhood lymphoid malignancy,' and have provided clues to the mechanism(s) of malignant transformation and tumor progression. Often, genes with possible roles in transcriptional regulation are translocated to sites of rearranging antigen receptor genes. A classic example occurs in B-cell leukemias and lymphomas, which invariably contain one of three specific translocations involving the c-myc proto-oncogene and an immunoglobulin receptor gene: the t(8;14) (q24;q32) or, less commonly, either the t(2;8)(p11;q24)
Address reprint requests to Raul C. Ribeiro, MD, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA (phone 901-5220300). Supported in part by grants CA 21765 and 20180 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).
acute leukemia
translocation
or the t(8;22)(q24;q11).2*3The involvement of c - m y in these translocations exemplifies proto-oncogene activation by means of chromosomal translocations. Similarly, molecular studies of T- cell leukemias and lymphomas have identified several chromosomal translocations involving genes that code for T-cell receptor (TCR) polypeptide chains. Among the nonrandom translocations in childhood T-cell ALL, the t(ll;l4)(pl3;qll) is the most c o r n ~ n o n ~This *~. translocation involves TCR alpha/delta (TCR A I D ) genes on chromosome 14 (14qll) and a region on band llp13 termed the T-ALL breakpoint cluster region (T-ALL bcr) where breakpoints cluster within a segment of only 2.5 kb6-13. Investigators have recently identified a gene telomeric of the llp13 T-ALL bcr that is highly expressed in cells carrying the t(ll;14)(p13;qll)'3*'4. Another translocation involves the same region on chromosome 14 but a different region on chromosome 11 (11p15), which carries a stage-specific differentiation gene (TTG-I, rhom-1 5-18.
351
352
R. C . RIBEIRO et d.
Despite abundant information regarding the molecular aspects of the two translocations, there is limited knowledge about the clinical and biologic characteristics of patients in whom they are present. We recently reported our experience with eight ALL patients having the t(l1;14)(p13;qll) and one having the t(ll;14)(p15;qll)s. Here we update our findings and review the literature.
A REVIEW OF CLINICAL AND BIOLOGIC FINDINGS From December 1979 to December 1990,938 children with newly diagnosed ALL were admitted to St. Jude Children’s Research Hospital. Of those, successful G-banding chromosome studies were available for 614 cases. Of the 148 cases known to be of the T-cell
n
0
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‘HA
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PEDIATRIC T-ALL WITH t(l1;14)
immunophenotype, G-banding chromosome studies were available for 110 cases. Among these, eight (7.2%) had the t(ll;l4)(pl3;qll)and one (1%) had the t(l1;14)(p15;qll) (Figure 1). The translocations were not found in any cases of non-T-cell ALL. All of the patients were placed on one of Total Therapy Studies X to XII'9920. During the same period, six additional patients with the t(11;14)(p13;qll) and four with the t(ll;l4)(pl5;qll) about whom adequate information was available were identified in the literature' 5*21-25. Presenting features of the 14 patients with T-cell ALL and the t(ll;l4)(pl3;qll) are summarized in Table 1. There were 11 boys and three girls aged 2 to 16 years (median, 7.5 years). These cases were characterized by high leukocyte counts (median, 193 x 109/L), high hemoglobin levels (median 121 g/L), and markedly elevated serum lactic dehydrogenase (LDH) levels (median, 3245 IU/L). Central nervous system (CNS) leukemia was present in two of eight patients and mediastinal mass in 11 of 13 patients. Of the 13 cases, lymphoblast morphology was FAB L1 in 10 and L2 in two cases. One case was reported as having L1/L2 morphology. Table 2 shows the immunophenotypes of leukemic cells from the 14 patients with the t(ll;l4)(pl3;qll). Cells from two patients were studied before monoclonal antibodies were available. Cells from all 13 tested expressed sheep erythrocyte receptors and/or CD2 (T11) surface antigen. Of 12 cases tested, 11 coexpressed CD4 and CD8, and four of 11 cases tested expressed CD3. None of the cells analyzed expressed surface immunoglobulinp-(Ig), cytoplasmic Ig or myelomonocytic markers. The clinical and laboratory features of five patients with T-cell ALL and t(l1;14)(p15;qll)are depicted in Table 3. All of them had T-cell ALL. In contrast to cases with the t(l1;14)(p13;qll), only one patient (case no. 15) had a markedly elevated leukocyte count at diagnosis. Two of four cases tested coexpressed CD4 and CD8 antigens, and two of three tested expressed CD3. The modal chromosome number of leukemic cells with either t(11;14) was 46 in 18 of the 19 patients. One had 92 chromosomes with a duplicate of a complex rearrangement between chromosomes 11 and 14. Case 1 had an additional unrelated line. In nine cases the t(11;14) was the only cytogenetic abnormality. The additional abnormalities included three cases with del(6q), one case each with del(9p) and i( 17q), and four cases of random translocations. No rearrangement was found in Ig heavy chain or kappa light chain gene loci among the 6 cases studied
353
(nos. 3-7 and 14). All samples analyzed showed rearrangement of the TCR beta (cases 5 , 6, 7 and 14) and TCR alpha (cases 7 and 14) gene loci. Among the patients from our institution, T-cell ALL cases with t(11;14) were more likely than those without the translocation to coexpress CD4 and CD8 surface antigens (7/7 vs. 35/86; p < 0.05). There were no salient clinical features, however, differentiating the T-cell cases with and without the t(ll;l4). There have been six adverse events among the nine patients with t(l1;14) from our institution: three CNS relapses (including the child with t(ll;l4)(pl5;qll)), one bone marrow relapse, and two cases of secondary acute myeloid leukemia. Three St. Jude patients are surviving event-free at 14+, 107.7+ and 108.5 months. At the times of publication, three reported patients were in disease-free survival periods of 9 + , 7 + and 39+ Remarkably, no patient with the t(11;14)(p15;qll) has sustained durable remission. The small number of patients with t(l1;14)(p13;qll) precluded meaningful statistical assessment of the prognostic importance of this translocation.
DISCUSSION We believe that there have been a sufficient number of consecutive immunologically and cytogenetically examined ALL cases to indicate that the t(11;14) (p13;qll) is specific for T-cell ALL. In our institution this translocation has been found in approximately 7% of T-cell ALL cases. The six cases described in the literature were also of the T-cell immunophenotype (Tables 1 and 2). The t(ll;l4)(pl5;qll) is rarer, occurring in fewer than 1YOof our T-cell ALL patients and in only four well documented reported cases. Haas et a1.26 have proposed a multi-step process model for childhood T-cell ALL wherein the specific translocations are not essential for malignant transformation but exert their influence on leukemia cell proliferation. Hence, the translocations should be associated with very large tumor burdens at diagnosis. Our reported findings in cases with t(11;14) did not support this proposal. Leukocyte counts and serum LDH levels, both indicators of leukemia burden, did not differ significantly between T-cell ALL cases with and without the translocations. Neither were there significant differences between the two groups in other presenting clinical, laboratory and molecular genetic features. Similarly, the presenting clinical and laboratory features of patients described in the
14
5
3 5 14 13 16 2
Age* (Yr)
-/M
-IF
WIM WIM W/M WIM
Race/gender
229 260 66.3 21.6 10.9 232.0
246 83 157 264 21.3 60.5 267 244
Leukocyte count ( x 109/L)
10
20 84 23 123
108
135 133
-
-
-
110 33
144 109 -
-
-
137
104
72 34 200
Platelets ( x 109/L)
104 61 16
Hemoglobin (g/L)
-
-
-
-
4ooo
3200 8650 3500 2290 3290 2100 575
Serum LDH (IlJ/L)
-
Yes No Yes Yes Yes
Ll/L2 L1 L1 L2 L1
- = not
Yes No Yes Yes Yes Yes Yes Yes
-
-
-
-
-
-
No No Yes No No
No Yes
No
CNS leukemia
Mediastinal mass
-
L1 L1 L2 L1 L1 L1 L1 L1
FAB classification
of references. assessed or not done. Abbreviations: AML, acute myeloid leukemia; Hem, hematologic relapse; CNS, central nervous system relapse; IF. induction failure.
t Survival data as of publication
* Age at diagnosis.
Published casest 91° 3 1021.22 12 1121.22 5 1223 4 1323 10 1423 14
6 7 8
5
1 2 3 4
St. Jude c a s e s 5
Patient number
Table 1 Clinical and laboratory features of 13 patients with T-cell ALL and the t(11;14)(p13;qll)
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+
+
4 9+ 7+ 39 33 0
106.3+ 20 4 4 12.6+
51
23 106.9
(mo)
Remission duration
-
-
-
-
-
~
+
75 108.5 82.5+ 107.7+ 24 44.6+ 25.8+ 14+
(mo)
Survival
Unknown IF
Unknown
Hem CNS CNS
AML
AML
Type of failure
ln P
W
5
3 5 1 1
4
5
-
-
-
~
-
-
-
~
-
~
-
-
1
-
-
-
-
-
4
4 26
~
-
-
15
-
96 96 80 86 86 96
24 2 4
2 2 1 1
-
-
CD7
5
-
CDlO
20 0 2
-
-
-
-
-
CDI9
-
CD20
= not assessed or not done. Abbreviations: Neg, negative; Pos, positive.
6 7 8 Published cases 9'O Neg 102I .22 1121.22 12223 1323 1423
42 6
~
HLA.DR
1 2 3
St. Jude cases'
Patient number
0
-
Neg 70 61 15
4
40 13 23 3 4
-
~
CDI
89
~
14
Pos 66 65
7 12 85 88 94 87 83 96
CD2/ E- R
~
0
5
Neg 9 61
8 7 17 58 22 5
-
-
CD3
% ' Positiue leukemic cells
Table 2 Immunophenotypes of leukemic cells from patients with T-cell ALL and the t(11;14)(p13;qll)
-
86
~
~
Pos 70
54 56 90 74 84 88 81 96
CD5
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15 92
Pos 35 0 74
66 78 24 30 62 84
-
-
CD4
POS 45 0 38 81 94
85 98 80 62 71 94
-
~
CD8
-
-
-
~
-
-
3 1
4
2
-
-
-
-
-
2 1 2 2
~
-
-
~
-
CD13
~
~
-
CDI5
-
-
-
0
3
0
2
-
-
-
(h
W
CD33
356
R. C. RlBElRO et a/.
Table 3 Clinical and laboratory features of 5 patients with T-cell ALL and the t(l1;14)(plS;qll) Feature
Patient
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I5 Age(y)/Gender Leukocyte count ( x 109/L) Hemoglobin (g/L) Platelet count ( x t09/L) Serum LDH levels (IU/L) FAB Classification Mediastinal mass CNS leukemia CD7 CD1 CD2/E-R CD3 CD5 CD4 CD8 Remission Duration (mo) Survival (mo) Type of failure Reference
3S/M 531
64 78 9990 LI No No 98% 10% 98% 95% 98% 33% 50% 2 31.9 t CNS (5)
16
17
18
19
16/F 16
15/M 11.6 I I9 35
6/M 21.4
1O/M
-
-
-
L2 No
-
Yes
-
Pos Neg Pos -
80% 58% 60% 31 ~
Hem (23)
63 85 120 11 Yes Yes 85% Neg Neg 80% Neg Neg 0 9 CNS (25)
+ Hem
Abbreviations: CNS, central nervous system relapse; Hem,hematologic relapse - = not assessed or not done.
Table 4 Leukemic cell karyotypes for T-cell ALL cases with the t(l1;14) Purient number
Karyotype
Translocation t(l1;14)(p13;qlI ) 1 46, XX, t( 11;14)(p13;ql1)/46, XX, de1(6)(q24) 2 46, XY, t( 1 1;l4)(p1 3;q 1 1) 3 46, XX, t( 11 ;14Xp13;q 1I ) 4 46, XY, t(11;14)(p13;qll) 5 46, XY, t( 11;l4)(pl3;qlI), t( 1;4Xp36;pI4)/ 46, XY, t( 1 I ;14)(p13;qlI ) 6 46, XY, t(l1;14)(p13;qlI) 7 46, XY, t( I 1;14)(p1 3;q 1 I ) 8 46, XY, t(ll;l4)(pl3;qll) 9 46, XY, t( I 1 ;14)(pl3;q1I), t( 1;12)(p31;ql3) 10 46, XY, t( 1 1;l4)(p13;q 13) II 92, XXYY, t( 1 1 ;14)(11;?)(qll ;p13;q25;?), t( I 1 ;14)(11;?)(q11;p13;q25;?) 12 46, XY, t(11;14)(p13: q l l ) 13 46, XX, t(I 1;14)(p13;qll),deI(6Xq21q25) 14 46, XY, t(l1;14)(p13;qI I), del(9Np22) Translocation t(l1;14)(plS;qlI) 15 46, XY, t(11;14)(p15;q11)/46,XY, de1(6)(q21),t(ll;l4)(plS;ql I ) 16 46, XX, 4q-, 4 q t , t(11;14)(p15;qll) 17 46, XY, - 15, t(ll;14)(p15;qlI), +der(l5)t(l5;?)(pll;?) 18 46, XY, i( 17q), t( 1 1 ;14)(plS;q1 I ) 19 46, XY, t(ll;l4)(plS;qll)
Reference
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PEDIATRIC T-ALL WITH t( 11 ;14)
357
literature (Table 1 and 3) did not differ from those is supported by observations of rearrangement among classically associated with T-cell ALLz7*z8. genes not involves in the specific trans location^^^. The influence of individual presenting features, Therefore, genes that are otherwise tightly regulated particularly specific translocations, on clinical out- may be activated on the rearranged chromosomes. In come of ALL patients has been difficult to establish. the t(ll;l4)(pl3;qll), the breakpoints on llp13 Our recent institutional studyz9 found that age, consistently fall within a region less than 2.5 Kb in leukocyte count, and T-cell immunophenotype were length”, suggesting that in these cases a deregulated each independently associated with outcome, but proto-oncogene plays a role in the development of translocations were not. No independently prognostic T-cell ALL’. A newly-discovered gene in the llp13 cytogenetic feature has been identified within the reg/ion, TTG-2 or rhom-2, encodes a cysteine-rich T-cell ALL group. Six adverse events have occurred protein with the “LIM” motif and is overexpressed in among the nine patients in our institution, and six had acute leukemia with the t(l1;14)(p13;ql l)I3*l4.Simioccurred among the nine patients described in the larly, the t(l1;14)(p15;qll) is accompanied by literature at the time they were reported. Two of our expression of another llp15 gene (TTG-I or rhom-1) patients have developed acute myeloid leukemia, a which is strongly homologous to the TTG-2 gene. rate similar to that generally seen in T-cell ALL TTG-I is expressed developmentally and segmentally .~~. casesL9. Additional studies will be required to in the murine CNS but not in normal T ~ e l l s ’ ~The determine whether patients with the t( 11;14) fare less TTG-1 and TTG-2 protein products show striking similarities, with approximately 50% amino acid well than do others with T-cell ALL. Reinherz et have proposed a three-stage identityI3-l4. They belong to the new class of scheme of thymocyte differentiation and maturation cysteine-rich proteins with the “LIM” motif which based on sequential expression of surface antigens. may be involved in DNA-protein, RNA-protein or Most T-cell malignancies can be classified by this protein-protein interactions. Hence, aberrant expresscheme as being at the early, intermediate or late stage sion of genes that are not normally involved in T-cell of thymocyte d i f f e r e n t i a t i ~ n ~All . ~ ~seven . St. Jude development may contribute to leukemogenesis in cases tested and five of eight described in the literature T-cell ALL. The molecular pathology underlying leukemogen(Tables 2 and 3) expressed a profile of membrane surface antigens (CD4+, CD8+, CD3 *) associated esis is a tantalizing puzzle. Our studies and those with intermediate- and later-stage thymocytes. Seven reviewed represent a continuing search for new St. Jude patients and six of the eight reported cases insights. presented with a mediastinal mass, which is associated with intermediate-stage thymocyte phenotypez7. Acknowledgements We thank Drs. Geoffrey Kitchingman and These findings suggested that the t(ll;l4)(pl3;qll) Rakesh Goorha for data on immunoglobulin and T cell receptor occurs exclusively in T-cell malignancies of inter- gene rearrangements, Peggy Vandiveer for preparation of the manuscript, and Sharon Naron for expert editorial review. mediate- or late-stage thymocyte maturation. Molecular study of the t(l1;14) has generated exciting new information. 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R. C. RIBEIRO e t a / .
6. Erikson, J., Williams, D. L., Finan, J., Nowell, P. C. and Croce, C. M. (1985). Locus of the a-chain of the T-cell receptor is split by chromosome translocation in T-cell leukemias. Science 229, 784786. 7. Lewis, W. H., Michalopoulos, E. E., Williams, D. L., Minden, M. D. and Mak, T. W. (1985). Breakpoints in the human T-cell antigen receptor a-chain locus in two T-cell leukaemia patients with chromosomal translocations. Nature 317, 544546. 8. Boehm, T., Buluwela, L., Williams, D., White, L. and Rabbitts, T. H. (1988). A cluster of chromosome llp13 translocations found via distinct D-D and D-D-J rearrangements of the human T-cell receptor S chain gene. EMBO J 7, 2011-2017. 9. Champagne, E., Takihara, Y., Sagman, U., de Sousa, J., Burrow, S., Lewis, W. H., Mak, T. W. and Minden, M. D. (1989). The T-cell receptor delta chain locus is disrupted in all the T-ALL associated t(l1;14)(p13;qll) translocation. Blood, 73, 1672-1 676. 10. Yoffe, G., Schneider, N., Van Dyk, L., Yang, CY-C, Siciliano, M., Buchanan, G., Capra, J. D. and Baer, R. (1989). The chromosome translocation (1 1 ;14)(p13;qlI) associated with T-cell acute lymphocytic leukemia: an 1 lp13 breakpoint cluster region. Blood, 74, 374379. 11. Foroni, L., Boehm, T., Lampert, F., Kaneko, Y., Raimondi, S . and Rabbitts, T. H. (1990). Multiple methylation-free islands flank a small breakpoint cluster region on llp13 in the t(11;14)(p13;qll)translocation. Genes, Chromosomes & Cancer, 1, 301-309. 12. Cheng, J.-T., Yang, C. Y.-C., Hernandez, J., Embrey, J. and Baer, R. (1990).The chromosome translocation (11;14)(p13;qll) associated with T-cell acute leukemia: asymetric diversification of the translocation junctions. J. Exp. Med., 171, 489-501. 13. Royer-Pokora, B., Loos, U. and Ludwig, W.-D. (1991). TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(l1;14) (p13;ql I), Oncogene, 6, 1887-1893. 14. Boehm, T., Foroni, L., Kaneko, Y., Perutz, M. F. and Rabbitts, T. H. (1991). The rhombotin family of cysteine-rich LIMdomain oncogenes: distinct members are involved in T-cell translocations to human chromosomes llp15 and llp13. froc. Natl. Acad. Sci. USA, 88, 4367-4371. 15. Takasaki, N., Kaneko, Y., Maseki, N., Sakurai, M., Shimamura, K. and Takayama, S. (1987). Hemophagocytic syndrome complicating T- cell acute lymphoblastic leukemia with a novel t(l1;14)(p15;qll) chromosome translocation. Cancer. 59, 424428. 16. Le Beau, M. M., McKeithan, T. W., Shima, E. A,, Goldman-Leikin, R. E., Chan, S . J., Bell, G . I., Rowley, J. D. and Diaz, M. 0. (1986). T-cell receptor a-chain gene is split in a human T-cell leukemia cell line with a t(l1;14)(pl5;qll). froc. Nail. Acad. Sci. USA, 83, 9744-9748. 17. Greenberg, J. M., Boehm, T., Sofroniew, M. V., Keynes, R. J., Barton, S. C., Norris, M. L., Surani, M. A,, Spillantini, M.-G. and Rabbitts, T. H. (1990). Segmental and developmental regulation of a presumptive T-cell oncogene in the central nervous system. Nature, 344,158-160. 18. McGuire, E. A., Davis, A. R., Korsmeyer, S. J. (1991). T-cell translocation gene 1 (Ttg-1)encodes a nuclear protein normally expressed in neural lineage cells. Blood, 77: 599-606. 19. Pui, C.-H., Behm, F. G., Raimondi, S. C., Dodge, R.K., George, S. L., Rivera, G. K., Mirro, J. Jr., Kalwinsky, D. K., Dahl, G. V., Murphy, S . B., Crist, W. M. and Williams, D. L. (1989). Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N. Engl. J. Med., 321, 136142. 20. Evans, W. E., Rodman, J. H., Relling, M. V., Crom, W. R., Rivera, G. K., Crist, W. M., and Pui, C.-H. (1991). Individualized doses of chemotherapy as a strategy to improve response for acute lymphocytic leukemia. Semin tiematol, 28, 15-21.
21. Lampert, F., Harbott, J., Ritterbach, J., Ludwig, W.-D., Fonatsch, C., Schwamborn, D., Stier, B., Gnekow, A,, Gerein, V., Stollmann, B., Jobke, A. and Janka-Schaub, G . (1988).T-cell acute childhood lymphoblastic leukemia with chromosome 14qll anomaly: a morphologic, immunologic, and cytogenetic analysis of 10 patients. Blut, 56, 117-123. 22. Harbott, J., Engel, R., Gerein, V., Schwamborn, D., Rudolph, R. and Lampert, F. (1986). (11;14) Translocation in three boys with acute lymphoblastic leukemia of T-cell immunophenotype. Blut, 52, 45-50. 23. Kaneko, Y.,Frizzera, G., Shikano, T., Kobayashi, H., Maseki, N. and Sakurai, M. (1989). Chromosomal and immunophenotypic patterns in T cell acute lymphoblastic leukemia (T ALL) and lymphoblastic lymphoma (LBL). Leukemia, 3, 886-892. 24. Huang, C. C., Hou, Y., Woods, L. K., Moore, G. E. and Minowada, J. (1974). Cytogenetic study of human lymphoid T-cell lines derived from lymphocytic leukemia. J. Natl. Cancer Inst., 53, 655-660. 25. Silva, M. L. M., Pombo de Oliveira, M. S., Valente, A. N., Abdelhay, E., Bouzas, L. F., Laun, L. and Ribeiro, R. C. (1991). CD7+, CD4-/CD8+ acute leukemia with the t(l1;14)(p15;ql I ) in a child. Cancer Genet Cytogenet, 56: 171-176. 26. Haas, M., Yu, A. and Gjerset, R. (1990). Characteristics of the leukemic cell in childhood acute lymphoblastic T cell leukemia at diagnosis. Leukemia, 4, 23C-234. 27. Crist, W. M., Shuster, J. J., Falletta, J., Pullen, D. J., Berard, C. W., Vietti, T. J., Alvarado, C. S., Roper, M. A,, Prasthofer, E. and Grossi, C. E. (1988). Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: A Pediatric Oncology Group Study. Blood, 72, 1891-1897. 28. Pui, C.-H., Behm, F. G., Singh, B., Schell, M. J., Williams, D. L., Rivera, G. K., Kalwinsky, D. K., Sandlund, J. T., Crist, W. M. and Raimondi, S . C. (1990). Heterogeneity of presenting features and their relation to treatment outcome in 120 children with T-cell acute lymphoblastic leukemia. Blood, 75, 174-1 79. 29. Rivera, G. K., Raimondi, S. C., Hancock, M. L., Behm, F. G., Pui, C.-H., Abromowitch, M., Mirro, J. Jr., Ochs, J. S., Look, A. T., Williams, D. L., Murphy, S. B., Dahl, G. V., Kalwinsky, D. K., Evans, W. E., Kun, L. E., Shone, J. V. and Crist, W. M. (1991). Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy. Lancet 337, 61-66. 30. Reinherz, E. L., Kung, P. C., Goldstein, G., Levey, R. H. and Schlossman, S. F. (1980). Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemia lymphoblasts of T-cell lineage. froc. Nail. Acud. Sci. USA, 77, 1588-1 592. 31. Toyonaga, B. and Mak, T. W. (1987). Genes of the T-cell antigen receptor in normal and malignant T cells. Ann Rev Immunol, 5, 585-620. 32. Aquilera, R. J., Shizuo, A., Okazaki, K. and Sakano, H. (1987). A pre-B cell nuclear protein that specifically interacts with the immunoglobulin V-J recombination sequences. Cell, 51, 909-9 17. 33. Tycko, B. and Sklar, J. (1990).Chromosomal translocations in lymphoid neoplasia: a reappraisal of the recombinase model. Cancer Cells, 2. 1-8. 34. Hope, T. J., Aguilera, R. J., Minie, M. E., Sakano, H. (1986). Endonucleolytic activity that cleaves immunoglobulin recombination sequences. Science, 231, 1141-1 145. 35. Aplan, P. D., Lombardi, D. P., Ginsberg, A. M., Cossman, J., Bertness, V. L. and Kirsch, 1. R. (1990).Disruption of the human SCL locus by “illegitimate” V-(D)-J recombinase activity. Science, 250, 14261429. 36. Rabbitts, T. H. and Boehm, T. (1991).Structural and functional chimerism results from chromosomal translocation in lymphoid tumors. Advances in Immunology, 50, 119-146.
Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children a
b
b
Raul C. Ribeiro , Susana C. Raimondi , Frederick G. Behm & Ching-Hon Pui
ab
a
Departments of Hematology-Oncology St. Jude Children's Research Hospital, and the Departments of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee, USA b
Departments of Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, and the Departments of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee, USA Published online: 01 Jun 2015.
To cite this article: Raul C. Ribeiro, Susana C. Raimondi, Frederick G. Behm & Ching-Hon Pui (1992) T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children, Leukemia & Lymphoma, 7:5-6, 351-358 To link to this article: http://dx.doi.org/10.3109/10428199209049790
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0 1992 Harwood Academic Publishers GmbH
Leukemia and Lymphoma, Vol. 7, pp. 351-358 Reprints available directly from the publisher Photocopying permitted by license only
Printed in the United Kingdom
T-cell Acute Lymphoblastic Leukemia with t(11;14) in Children RAUL C. RIBEIRO,' SUSANA C. RAIMONDI,' FREDERICK G. BEHM,2 and CHING-HON PUI'v2
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'Departments of Hematology-Oncology, 2Pathology and Laboratory Medicine, St. Jude Children's Research Hospital, and the Departments of Pediatrics and Pathology, University of Tennessee, Memphis, College of Medicine, Memphis, Tennessee, U.S.A. (Received 25 February 1992)
We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(1 1;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(ll;l4), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t( 11;14)(p13;qll) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance. KEY WORDS:
T- ALL
t(l1;14)
Pediatric ALL
INTRODUCTION Chromosomal translocations are common findings in childhood lymphoid malignancy,' and have provided clues to the mechanism(s) of malignant transformation and tumor progression. Often, genes with possible roles in transcriptional regulation are translocated to sites of rearranging antigen receptor genes. A classic example occurs in B-cell leukemias and lymphomas, which invariably contain one of three specific translocations involving the c-myc proto-oncogene and an immunoglobulin receptor gene: the t(8;14) (q24;q32) or, less commonly, either the t(2;8)(p11;q24)
Address reprint requests to Raul C. Ribeiro, MD, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA (phone 901-5220300). Supported in part by grants CA 21765 and 20180 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).
acute leukemia
translocation
or the t(8;22)(q24;q11).2*3The involvement of c - m y in these translocations exemplifies proto-oncogene activation by means of chromosomal translocations. Similarly, molecular studies of T- cell leukemias and lymphomas have identified several chromosomal translocations involving genes that code for T-cell receptor (TCR) polypeptide chains. Among the nonrandom translocations in childhood T-cell ALL, the t(ll;l4)(pl3;qll) is the most c o r n ~ n o n ~This *~. translocation involves TCR alpha/delta (TCR A I D ) genes on chromosome 14 (14qll) and a region on band llp13 termed the T-ALL breakpoint cluster region (T-ALL bcr) where breakpoints cluster within a segment of only 2.5 kb6-13. Investigators have recently identified a gene telomeric of the llp13 T-ALL bcr that is highly expressed in cells carrying the t(ll;14)(p13;qll)'3*'4. Another translocation involves the same region on chromosome 14 but a different region on chromosome 11 (11p15), which carries a stage-specific differentiation gene (TTG-I, rhom-1 5-18.
351
352
R. C . RIBEIRO et d.
Despite abundant information regarding the molecular aspects of the two translocations, there is limited knowledge about the clinical and biologic characteristics of patients in whom they are present. We recently reported our experience with eight ALL patients having the t(l1;14)(p13;qll) and one having the t(ll;14)(p15;qll)s. Here we update our findings and review the literature.
A REVIEW OF CLINICAL AND BIOLOGIC FINDINGS From December 1979 to December 1990,938 children with newly diagnosed ALL were admitted to St. Jude Children’s Research Hospital. Of those, successful G-banding chromosome studies were available for 614 cases. Of the 148 cases known to be of the T-cell
n
0
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‘HA
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PEDIATRIC T-ALL WITH t(l1;14)
immunophenotype, G-banding chromosome studies were available for 110 cases. Among these, eight (7.2%) had the t(ll;l4)(pl3;qll)and one (1%) had the t(l1;14)(p15;qll) (Figure 1). The translocations were not found in any cases of non-T-cell ALL. All of the patients were placed on one of Total Therapy Studies X to XII'9920. During the same period, six additional patients with the t(11;14)(p13;qll) and four with the t(ll;l4)(pl5;qll) about whom adequate information was available were identified in the literature' 5*21-25. Presenting features of the 14 patients with T-cell ALL and the t(ll;l4)(pl3;qll) are summarized in Table 1. There were 11 boys and three girls aged 2 to 16 years (median, 7.5 years). These cases were characterized by high leukocyte counts (median, 193 x 109/L), high hemoglobin levels (median 121 g/L), and markedly elevated serum lactic dehydrogenase (LDH) levels (median, 3245 IU/L). Central nervous system (CNS) leukemia was present in two of eight patients and mediastinal mass in 11 of 13 patients. Of the 13 cases, lymphoblast morphology was FAB L1 in 10 and L2 in two cases. One case was reported as having L1/L2 morphology. Table 2 shows the immunophenotypes of leukemic cells from the 14 patients with the t(ll;l4)(pl3;qll). Cells from two patients were studied before monoclonal antibodies were available. Cells from all 13 tested expressed sheep erythrocyte receptors and/or CD2 (T11) surface antigen. Of 12 cases tested, 11 coexpressed CD4 and CD8, and four of 11 cases tested expressed CD3. None of the cells analyzed expressed surface immunoglobulinp-(Ig), cytoplasmic Ig or myelomonocytic markers. The clinical and laboratory features of five patients with T-cell ALL and t(l1;14)(p15;qll)are depicted in Table 3. All of them had T-cell ALL. In contrast to cases with the t(l1;14)(p13;qll), only one patient (case no. 15) had a markedly elevated leukocyte count at diagnosis. Two of four cases tested coexpressed CD4 and CD8 antigens, and two of three tested expressed CD3. The modal chromosome number of leukemic cells with either t(11;14) was 46 in 18 of the 19 patients. One had 92 chromosomes with a duplicate of a complex rearrangement between chromosomes 11 and 14. Case 1 had an additional unrelated line. In nine cases the t(11;14) was the only cytogenetic abnormality. The additional abnormalities included three cases with del(6q), one case each with del(9p) and i( 17q), and four cases of random translocations. No rearrangement was found in Ig heavy chain or kappa light chain gene loci among the 6 cases studied
353
(nos. 3-7 and 14). All samples analyzed showed rearrangement of the TCR beta (cases 5 , 6, 7 and 14) and TCR alpha (cases 7 and 14) gene loci. Among the patients from our institution, T-cell ALL cases with t(11;14) were more likely than those without the translocation to coexpress CD4 and CD8 surface antigens (7/7 vs. 35/86; p < 0.05). There were no salient clinical features, however, differentiating the T-cell cases with and without the t(ll;l4). There have been six adverse events among the nine patients with t(l1;14) from our institution: three CNS relapses (including the child with t(ll;l4)(pl5;qll)), one bone marrow relapse, and two cases of secondary acute myeloid leukemia. Three St. Jude patients are surviving event-free at 14+, 107.7+ and 108.5 months. At the times of publication, three reported patients were in disease-free survival periods of 9 + , 7 + and 39+ Remarkably, no patient with the t(11;14)(p15;qll) has sustained durable remission. The small number of patients with t(l1;14)(p13;qll) precluded meaningful statistical assessment of the prognostic importance of this translocation.
DISCUSSION We believe that there have been a sufficient number of consecutive immunologically and cytogenetically examined ALL cases to indicate that the t(11;14) (p13;qll) is specific for T-cell ALL. In our institution this translocation has been found in approximately 7% of T-cell ALL cases. The six cases described in the literature were also of the T-cell immunophenotype (Tables 1 and 2). The t(ll;l4)(pl5;qll) is rarer, occurring in fewer than 1YOof our T-cell ALL patients and in only four well documented reported cases. Haas et a1.26 have proposed a multi-step process model for childhood T-cell ALL wherein the specific translocations are not essential for malignant transformation but exert their influence on leukemia cell proliferation. Hence, the translocations should be associated with very large tumor burdens at diagnosis. Our reported findings in cases with t(11;14) did not support this proposal. Leukocyte counts and serum LDH levels, both indicators of leukemia burden, did not differ significantly between T-cell ALL cases with and without the translocations. Neither were there significant differences between the two groups in other presenting clinical, laboratory and molecular genetic features. Similarly, the presenting clinical and laboratory features of patients described in the
14
5
3 5 14 13 16 2
Age* (Yr)
-/M
-IF
WIM WIM W/M WIM
Race/gender
229 260 66.3 21.6 10.9 232.0
246 83 157 264 21.3 60.5 267 244
Leukocyte count ( x 109/L)
10
20 84 23 123
108
135 133
-
-
-
110 33
144 109 -
-
-
137
104
72 34 200
Platelets ( x 109/L)
104 61 16
Hemoglobin (g/L)
-
-
-
-
4ooo
3200 8650 3500 2290 3290 2100 575
Serum LDH (IlJ/L)
-
Yes No Yes Yes Yes
Ll/L2 L1 L1 L2 L1
- = not
Yes No Yes Yes Yes Yes Yes Yes
-
-
-
-
-
-
No No Yes No No
No Yes
No
CNS leukemia
Mediastinal mass
-
L1 L1 L2 L1 L1 L1 L1 L1
FAB classification
of references. assessed or not done. Abbreviations: AML, acute myeloid leukemia; Hem, hematologic relapse; CNS, central nervous system relapse; IF. induction failure.
t Survival data as of publication
* Age at diagnosis.
Published casest 91° 3 1021.22 12 1121.22 5 1223 4 1323 10 1423 14
6 7 8
5
1 2 3 4
St. Jude c a s e s 5
Patient number
Table 1 Clinical and laboratory features of 13 patients with T-cell ALL and the t(11;14)(p13;qll)
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+
+
4 9+ 7+ 39 33 0
106.3+ 20 4 4 12.6+
51
23 106.9
(mo)
Remission duration
-
-
-
-
-
~
+
75 108.5 82.5+ 107.7+ 24 44.6+ 25.8+ 14+
(mo)
Survival
Unknown IF
Unknown
Hem CNS CNS
AML
AML
Type of failure
ln P
W
5
3 5 1 1
4
5
-
-
-
~
-
-
-
~
-
~
-
-
1
-
-
-
-
-
4
4 26
~
-
-
15
-
96 96 80 86 86 96
24 2 4
2 2 1 1
-
-
CD7
5
-
CDlO
20 0 2
-
-
-
-
-
CDI9
-
CD20
= not assessed or not done. Abbreviations: Neg, negative; Pos, positive.
6 7 8 Published cases 9'O Neg 102I .22 1121.22 12223 1323 1423
42 6
~
HLA.DR
1 2 3
St. Jude cases'
Patient number
0
-
Neg 70 61 15
4
40 13 23 3 4
-
~
CDI
89
~
14
Pos 66 65
7 12 85 88 94 87 83 96
CD2/ E- R
~
0
5
Neg 9 61
8 7 17 58 22 5
-
-
CD3
% ' Positiue leukemic cells
Table 2 Immunophenotypes of leukemic cells from patients with T-cell ALL and the t(11;14)(p13;qll)
-
86
~
~
Pos 70
54 56 90 74 84 88 81 96
CD5
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15 92
Pos 35 0 74
66 78 24 30 62 84
-
-
CD4
POS 45 0 38 81 94
85 98 80 62 71 94
-
~
CD8
-
-
-
~
-
-
3 1
4
2
-
-
-
-
-
2 1 2 2
~
-
-
~
-
CD13
~
~
-
CDI5
-
-
-
0
3
0
2
-
-
-
(h
W
CD33
356
R. C. RlBElRO et a/.
Table 3 Clinical and laboratory features of 5 patients with T-cell ALL and the t(l1;14)(plS;qll) Feature
Patient
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I5 Age(y)/Gender Leukocyte count ( x 109/L) Hemoglobin (g/L) Platelet count ( x t09/L) Serum LDH levels (IU/L) FAB Classification Mediastinal mass CNS leukemia CD7 CD1 CD2/E-R CD3 CD5 CD4 CD8 Remission Duration (mo) Survival (mo) Type of failure Reference
3S/M 531
64 78 9990 LI No No 98% 10% 98% 95% 98% 33% 50% 2 31.9 t CNS (5)
16
17
18
19
16/F 16
15/M 11.6 I I9 35
6/M 21.4
1O/M
-
-
-
L2 No
-
Yes
-
Pos Neg Pos -
80% 58% 60% 31 ~
Hem (23)
63 85 120 11 Yes Yes 85% Neg Neg 80% Neg Neg 0 9 CNS (25)
+ Hem
Abbreviations: CNS, central nervous system relapse; Hem,hematologic relapse - = not assessed or not done.
Table 4 Leukemic cell karyotypes for T-cell ALL cases with the t(l1;14) Purient number
Karyotype
Translocation t(l1;14)(p13;qlI ) 1 46, XX, t( 11;14)(p13;ql1)/46, XX, de1(6)(q24) 2 46, XY, t( 1 1;l4)(p1 3;q 1 1) 3 46, XX, t( 11 ;14Xp13;q 1I ) 4 46, XY, t(11;14)(p13;qll) 5 46, XY, t( 11;l4)(pl3;qlI), t( 1;4Xp36;pI4)/ 46, XY, t( 1 I ;14)(p13;qlI ) 6 46, XY, t(l1;14)(p13;qlI) 7 46, XY, t( I 1;14)(p1 3;q 1 I ) 8 46, XY, t(ll;l4)(pl3;qll) 9 46, XY, t( I 1 ;14)(pl3;q1I), t( 1;12)(p31;ql3) 10 46, XY, t( 1 1;l4)(p13;q 13) II 92, XXYY, t( 1 1 ;14)(11;?)(qll ;p13;q25;?), t( I 1 ;14)(11;?)(q11;p13;q25;?) 12 46, XY, t(11;14)(p13: q l l ) 13 46, XX, t(I 1;14)(p13;qll),deI(6Xq21q25) 14 46, XY, t(l1;14)(p13;qI I), del(9Np22) Translocation t(l1;14)(plS;qlI) 15 46, XY, t(11;14)(p15;q11)/46,XY, de1(6)(q21),t(ll;l4)(plS;ql I ) 16 46, XX, 4q-, 4 q t , t(11;14)(p15;qll) 17 46, XY, - 15, t(ll;14)(p15;qlI), +der(l5)t(l5;?)(pll;?) 18 46, XY, i( 17q), t( 1 1 ;14)(plS;q1 I ) 19 46, XY, t(ll;l4)(plS;qll)
Reference
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PEDIATRIC T-ALL WITH t( 11 ;14)
357
literature (Table 1 and 3) did not differ from those is supported by observations of rearrangement among classically associated with T-cell ALLz7*z8. genes not involves in the specific trans location^^^. The influence of individual presenting features, Therefore, genes that are otherwise tightly regulated particularly specific translocations, on clinical out- may be activated on the rearranged chromosomes. In come of ALL patients has been difficult to establish. the t(ll;l4)(pl3;qll), the breakpoints on llp13 Our recent institutional studyz9 found that age, consistently fall within a region less than 2.5 Kb in leukocyte count, and T-cell immunophenotype were length”, suggesting that in these cases a deregulated each independently associated with outcome, but proto-oncogene plays a role in the development of translocations were not. No independently prognostic T-cell ALL’. A newly-discovered gene in the llp13 cytogenetic feature has been identified within the reg/ion, TTG-2 or rhom-2, encodes a cysteine-rich T-cell ALL group. Six adverse events have occurred protein with the “LIM” motif and is overexpressed in among the nine patients in our institution, and six had acute leukemia with the t(l1;14)(p13;ql l)I3*l4.Simioccurred among the nine patients described in the larly, the t(l1;14)(p15;qll) is accompanied by literature at the time they were reported. Two of our expression of another llp15 gene (TTG-I or rhom-1) patients have developed acute myeloid leukemia, a which is strongly homologous to the TTG-2 gene. rate similar to that generally seen in T-cell ALL TTG-I is expressed developmentally and segmentally .~~. casesL9. Additional studies will be required to in the murine CNS but not in normal T ~ e l l s ’ ~The determine whether patients with the t( 11;14) fare less TTG-1 and TTG-2 protein products show striking similarities, with approximately 50% amino acid well than do others with T-cell ALL. Reinherz et have proposed a three-stage identityI3-l4. They belong to the new class of scheme of thymocyte differentiation and maturation cysteine-rich proteins with the “LIM” motif which based on sequential expression of surface antigens. may be involved in DNA-protein, RNA-protein or Most T-cell malignancies can be classified by this protein-protein interactions. Hence, aberrant expresscheme as being at the early, intermediate or late stage sion of genes that are not normally involved in T-cell of thymocyte d i f f e r e n t i a t i ~ n ~All . ~ ~seven . St. Jude development may contribute to leukemogenesis in cases tested and five of eight described in the literature T-cell ALL. The molecular pathology underlying leukemogen(Tables 2 and 3) expressed a profile of membrane surface antigens (CD4+, CD8+, CD3 *) associated esis is a tantalizing puzzle. Our studies and those with intermediate- and later-stage thymocytes. Seven reviewed represent a continuing search for new St. Jude patients and six of the eight reported cases insights. presented with a mediastinal mass, which is associated with intermediate-stage thymocyte phenotypez7. Acknowledgements We thank Drs. Geoffrey Kitchingman and These findings suggested that the t(ll;l4)(pl3;qll) Rakesh Goorha for data on immunoglobulin and T cell receptor occurs exclusively in T-cell malignancies of inter- gene rearrangements, Peggy Vandiveer for preparation of the manuscript, and Sharon Naron for expert editorial review. mediate- or late-stage thymocyte maturation. Molecular study of the t(l1;14) has generated exciting new information. 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