“Jumping translocation” in a 17-month-old child with mixed-lineage leukemia

"Jumping Translocation" in a 17-Month-Old Child with Mixed-Lineage Leukemia Susana Ben-Neriah, Ayala Abramov, Israela Lerer, Aaron Polliack, Rachel Leizerowitz, Ruth Rabinowitz, and Dvorah Abeliovich

ABSTRACT: A 17-month-old child with acute biphenotypic (pre B-ALL/myelomonocytic) leukemia is reported. Extensive cytogenetic analysis performed at various stages of the disease revealed a clonal evolution at the time of initial diagnosis with two types of abnormal clones, one with trisomy 22 and two other related clones with trisomy 22 plus partial trisomy of the long arm of chromosome 1 associated with the telomeric segment of either chromosome 20q or 21p. At the time of relapse the only abnormal clone involved trisomy 22 and partial trisomy of lq, but this time in association with the telomeric segment of 14p. The unique feature of these translocations is discussed and the possibility of the correlation between the different chromosomal abnormalities and the expression of biphenotypic markers is raised.

INTRODUCTION Acute l e u k e m i a in w h i c h the blasts express surface markers of more than one lineage has been termed acute m i x e d lineage leukemia [1]. Other terms such as b i p h e n o t y p i c leukemia [2], hybrid leukemia [3], lineage promiscuity, or infidelity have been used to describe similar p h e n o m e n a [4]. S i m u l t a n e o u s dual staining of i n d i v i d u a l leukemic blasts for surface antigens of both m y e l o i d and l y m p h o i d cells [5] supports the view that most of the acute m i x ed lineage leukemias result from malignant transformation of a single cell. The genetic m e c h a n i s m u n d e r l y i n g the coexpression of myeloid and l y m p h o i d markers is still not well understood, however, there are two possibilities. First, that the cell may have been at an early and primitive stage of h em o p o ei t i c differentiation at the time of the neoplastic transformation. Alternatively, it is possible that the process of transformation induces alterations in cell regulation that result in the coexpression of surface antigens of more than one cell lineage. In some rare cases, however, it is probable that the origin of the mixed lineage leukemia is truly biclonal. Paietta [61 recently s u m m a r i z e d the most frequently encountered chromosomal changes in mixed lineage leukemias and from this report it is evident that most of the published Department of Human Genetics (S. B.-N.. I. L., D. A.), Hadassah UniversityHospital, Jerusalem; Department of Pediatrics (A. A.). Shaarei-ZedekMedical Center, lerusalem: Lymphoma-LeukemiaUnit (A. P., R. L.), Department of llematology, Hadassah University Hospital, Jerusalem; and Hubert 11. ttumphrey Center for Experimental Medicine and Cancer Research (R. R.) Hadassah University Medical Center. Hebrew University, Jerusalem. Israel. Address reprint requests to: Dvorah Abeliovich, Department of Human Genetics, Hadassah University Hospital, Kiryat Hadassah P.O.B. 12000, Jerusalem 91120, Israel. Received February 1, 1991; accepted April 22, 1991.

223 © 1991 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas. New York, NY 10010

Cancer Genet Cytogenet 56:223 229 (1991) 0165-4608/91/$03.50

224

s. Ben-Neriah et al. cases had one abnormal clone with or without subsequent clonal evolution [3, 5], whereas unrelated abnormal clones were only rarely found [7]. In this report we describe a study of bone marrow cells from a child with acute b i p h e n o t y p i c (pre-B l y m p h o b l a s t i c / m y e l o m o n o c y t i c ) leukemia. Cytogenetic analysis at the time of diagnosis and at relapse revealed trisomy 22 in all the abnormal m e t a p h a s e s with clonal evolution, w h i c h resulted in partial trisomy of l q due to a " j u m p i n g translocation" of l q to the telomeric segments of different recipient chromosomes (14p, 20q, 21p). This unique translocation has not been, to the best of our knowledge, described in association with m i x e d lineage leukemia.

Case Report This 17-month-old child was first admitted in October 1988 for evaluation of severe anemia and high fever of 2 weeks duration. Physical examination revealed generalized l y m p h a d e n o p a t h y , mild hepatosplenomegaly, and gingival hypertrophy. Acute l e u k e m i a was diagnosed and laboratory investigation established this to be an acute m i x e d lineage leukemia. The child was treated according to the BFM protocol (1987), (which i n c l u d e d i n d u c t i o n therapy with cytosine arabinoside (Ara C), Daunomycin, and Etoposide (VP16)) and achieved complete remission. Consolidation c h e m o t h e r a p y was a d m i n i s t e r e d including prednisone, 6-thioguanine, Vincrisfine, Doxorubicin, Ara C, and c y c l o p h o s p h a m i d e . Complete remission was maintained and in May 1989 an allogeneic bone marrow transplantion was performed. Three weeks later there was graft rejection and autologous bone marrow transplantion was done using marrow cryopreserved at the time of remission. Remission lasted until November 1989 w h e n relapse occurred, followed by death 1 month later due to progressive l e u k e m i a and sepsis.

Laboratory Investigation On a d m i s s i o n the p e r i p h e r a l blood disclosed severe n o r m o c h r o m i c normocytic anemia of 4 g/dL. The WBC count was 15.4 × 109/L, with 80% blasts, while the platelet count was 50 × 109/L. Serum LDH levels were m a r k e d l y elevated (3750/.t/L), while other liver function tests were w i t h i n normal limits. Serum uric acid and muramidase levels were w i t h i n normal limits. No leukemic cells were evident in the CNS fluid. At the time of relapse, in November 1989, the leukocyte count was 68 × 109/L with 15 x 109/L thrombocytes and severe anemia of 6 g/dl.

Cell Morphology At diagnosis, most blasts in the peripheral blood and bone marrow were myeloblasts and only a few resembled lymphoblasts. Almost all cytochemical stains for both l y m p h o i d and m y e l o i d cells were negative in the vast majority of the cells and only 5% stained positively with Sudan black and m y e l o p e r o x i d a s e (MPO), while there was diffuse but not focal paranuclear staining with acid phosphatase. On relapse, the blast m o r p h o l o g y was c o m p a t i b l e with ALL, FAB type 2, and no myeloblasts were seen.

Using monoclonal antibodies the following i m m u n o p h e n o t y p e was seen at the time of diagnosis: HLA DR(90%), CD19(95%), CD14(95%), CD33(95%), CD13(95%); CD20, CD10, and CD3 were all negative. Based on the presence of myelo-monocytic markers (CD14 and CD33) in the presence of a l y m p h o i d marker (CD19), the diagnosis of mixed lineage leukmnia (pre-B l y m p h o b l a s t i c / m y e l o m o n o c y t i c ) was established. At the time of relapse the following p h e n o t y p e was seen: HLA DR(92%),

225

Jumping Translocation in 17-Month-Old Child

Table 1

Chromosomal analysis at various stages of the disease

Diagnosis (n = 35) 46,XY 47,XY, + 22 47,XY,+ 22,- 20,+ der(20lt(1;20l(q2?;ql?) 47,XY,+ 22,- 21,+der(21)t(1;21)(q2?~pl?) Remission (n = 30) 46,XY Relapse (n = 30) 46,XY 47.XY,+22, 14, + der(14)t(1;14)(ql 1;p11)

9% 65% 23% 3% 100% 6% 94%

CD19(80%), CD34(83%). M y e l o m o n o c y t i c markers (CD33, CD14, CD13, and CALLA (CD10)) were negative this time. Unfortunately, anti-TdT immunofluorescent studies were not done in this case.

Cytogenetic Analysis The cytogenetic study was performed according to the technique described by Michaeli et al. using the c o n d i t i o n e d m e d i u m derived from the h u m a n b l a d d e r carcinoma cell line 5637 [8]. Results are s u m m a r i z e d in Table 1. At diagnosis, 35 metaphases were analysed; 91% of t h e m were abnormal. All abnormal metaphases had 47 c h r o m o s o m e s with trisomy 22 but in 26% of the metaphases clonal evolution was observed with translocation of lq2? onto the distal end of c h r o m o s o m e 20q (Fig. 1). In one m e t a p h a s e the same portion of lq2? was translocated onto the terminal region of 21p (Fig. 2). On remission, 30 metaphases were analysed all of w h i c h had a normal karyotype. On relapse, 30 cells were examined. Only 6% had a normal karyotype and the a b n o r m a l clone had trisomy 22 with partial trisomy of l q due to a translocation of l q l l to the distal region of 14p (Fig. 3). The breakpoint at l q at the time of diagnosis was distal to the heterochromatic region, whereas at relapse it was p r o x i m a l to this region. Cytogenetic analysis of skin fibroblasts revealed a normal karyotype, 46,XY, thereby excluding the possibility of constitutional trisomy 22 mosaicism.

DISCUSSION This 17-month-old child had a m i x e d lineage leukemia of pre-B A L L / m y e l o m o n o cytic type. A l t h o u g h double labeling was not performed the overlap in the percentage of blasts reacting with l y m p h o i d and myeloid-associated antibodies i n d i c a t e d that most blasts had both l y m p h o i d and m y e l o i d surface markers at the time of diagnosis. At relapse the cells were p r e d o m i n a n t l y l y m p h o i d in nature. The cytogenetic findings described here are consistent with clonal evolution of the trisomy 22 clone to a more c o m p l e x karyotype, w h i c h i n c l u d e d an a d d i t i o n a l partial t r i s o m y to the long arm of c h r o m o s o m e 1. The partial trisomy of l q appears to be the result of an u n b a l a n c e d translocation of l q to the very distal region (telomere) of 14p, 20q, and 21p. This type of translocation has been defined as m u l t i p l e telomeric associations [9] and termed a " j u m p i n g translocation" [10]. "Jumping translocation" has been described in only a few cases of l e u k e m i a / l y m p h o m a , most ot w h i c h were of B-lineage. In 1988, Fitzgerald and Morris [11] described it in a patient

226

s. Ben-Neriah et al.

4

10

8

13

14

lq

20

Figure 1

15

12

11

-J i l&

2t

5

X

M 17

22

18

Y

Abnormal clone at diagnosis: 47.XY,+22, 20,+der(20)t(1;20l(q2?:ql?l.

with acute B-type lymphoblastic leukemia, who had an u n b a l a n c e d translocation of 1 q l l - q t e r with the telomeres of 11q, 13q, 15q, 18p, 21p, and Xp; in 1984 Whang-Peng et al. [12] described a patient with AIDS-associated Burkitt l y m p h o m a who had duplication of l q 2 1 - q 3 2 or 1q21-q44 in addition to the typical t(8;14). In some cells l q 2 1 - q 4 4 was translocated to the telomeres of 4q or 19q. Raimondi et al. [9] described a patient with ALL, (FAB-L1) with partial trisomy of 1q11-qter, which was translocated to the terminal region of 2q, 13q, and 16q. Shinohara and Nomura reported a similar case in 1988 [10]. Most recently, Shippey et al. [13] described a patient with B-lineage ALL who had a t(4;11) and a " j u m p i n g translocation" of l q l l or 1q21 to the distal end of 4q, 11q, 16q, or 19q, which resulted in partial trisomy for lq. Based on the few cases recorded who had a similar type of translocation it seems that a break in the long arm of chromosome 1, adjacent to the heterochromatin (lqh), either at the proximal or at the distal side, exposes an unstable region that tends to associate with telomeres, or very close to them, of various chromosomes. The exact site of the association cannot be determined cytogenically, but might be defined more accurately by in situ hybridization, using the repetitive DNA sequence specific for the h u m a n telomeres as a probe [14]. The origin of l q in the translocations is not known. It is possible that the development of a clone with complete trisomy 1 was the first step in the evolution of the translocation, followed by a subsequent break adjacent to lqh. Whereas the long arm was translocated to a telomere of a recipient chromosome, the short arm with the centromere was lost due to the missing telo-

227

Jumping Translocation in 17-Month-Old Child

li 2

III-

!|

+ 4

3

5

i r t ! - i t iii- t l - " - i l i 6

7

8

9

-ii13

14

15

ID

11

12

ii i - : i t 16

X

ii-

17

18

i 19

Figure 3

20

21

22

Y

47,XY,+22,-21,+der(21)t(1;21)(q2?;pl?).

mere. The m u l t i p l e telomeric association could have evolved either if the translocated l q " j u m p e d " from one recipient c h r o m o s o m e to another or alternatively if the same sequence of events, starting from a trisomy 1 clone and a break at lq, repeated itself. In the latter instance one has to assume the presence of a clastogenic factor that specifically affects the heterochromatic region of lq. In 1984 Fitzgerald and Morris [11] suggested that viral infection could be involved in the formation of a " j u m p i n g translocation", while more recently Haas [15] also i m p l i e d that centromeric heterochromatin instability of chromosomes 1, 9, and 16 is i n d u c e d by viruses in the c o m m o n variable i m m u n o d e f i c i e n c y syndrome. The fact that two different breakpoints exist at l q in two abnormal clones in our patient as well as in the case reported by S h i p p e y et al. [13] support the hypothesis of i n d e p e n dent formation of the translocations. In the present case the subclone with t(1;14)(q11;p11) could either have d e v e l o p e d in the early stage of the disease as a m i n o r clone or m a y have evolved after the administration of chemotherapy. However, whatever the cause, it could eventually have become the p r e d o m i n a n t clone due to growth advantage [16]. In the occasional reported cases with a " j u m p i n g translocation", the recipient c h r o m o s o m e s 2q, 11q, 16q, and 13q seemed to be overrepresented. In our patient the telomeres that were involved in the translocation were of 14p, 20q, and 21p and until n o w none of t h e m have been described as recipients in " j u m p i n g translocation". Our case is also u n i q u e in two other respects, namely, that this was a m i x e d lineage leukemia, w h i c h in itself is rare and because this child appears to be the youngest ot all the patients reported in the literature with a " j u m p i n g translocation".

228

s. Ben-Neriah et al.

t

6

7

-~

8

14

13

-

19

Figure 3

4

3

2

g

15

10

11

16

5

12

17

X

18

- 4 .

20

....

21

22

Y

Abnormal clone at relapse: 47,XY,÷22,-14, der(14)t(1;14)(q11;p11).

It is t e m p t i n g to suggest that the i m m u n o p h e n o t y p e of the blasts correlates with the cytogenetic abnormalities and that each of the chromosomal abnormalities is r e s p o n s i b l e for the expression of either l y m p h o c y t i c or m y e l o i d markers. Chromosome 1 i n v o l v e m e n t is frequent in both hematologic and solid tumors [17, 18] and has been found as a s e c o n d a r y change in ALL [9, 18]. The presence of a " j u m p i n g t r a n s l o c a t i o n " has been encountered in association with B-lineage leukemia in 4 of the 5 reported cases. Trisomy 22, on the other hand, is one of the rare trisomies found in hematologic malignancies and has been mostly described in AML [19]. However, it has been d i s p u t e d w h e t h e r trisomy 22 represents a primary cytogenetic change or is, in fact, a s e c o n d a r y event in inv(16) in AML M4 eosinophilia [20]. In our patient inv(16) was not seen; however, when the disease relapsed the blasts lost their m y e l o i d markers w h i l e the trisomy 22 still persisted. This does not support the view that trisomy 22 per se is responsible for the expression of the m y e l o i d markers. We are grateful to Dr. G. Rechavi for his help in the immunophenotyping. This study was supported by the Paul Erlich Center for the Study of Leukemic and Normal Lymphocytes (A. P.). REFERENCES

1. Stass SA, Mirro J (1986): Lineage heterogeneity in acute leukaemia: acute mixed-lineage leukaemia and lineage switch. Clinics in Haematology 15:811-827.

J u m p i n g T r a n s l o c a t i o n in 1 7 - M o n t h - O l d C h i l d

229

2. Parentesis J, Ramsay N, Brunniug R, Kersey J, Filipowich A (1983): Biphenotypic leukemia: Immunologic and morphologic evidence for a common lymphoid-myeloid progenitor in human. J Pediatr 102:63-67. 3. Gale RP, Ben-Bassat I (1987): Hybrid acute leukemia. Br J Haematol 65:261-264. 4. Greaves MF, Chan LC, Furley AJW, Watt SM, Molgaard HV (1986): Lineage promiscuity in hemopoietic differentiation and leukemia. Blood 67:1-11. 5. Mirro J, Zipf TF, Pui C-H, Kitchingman G, Williams D, Melvin S, Murphy SB, Stass S (1985): Acute mixed lineage leukemia: Clinicopathologic correlations and prognostic significance. Blood 66:1115-1123. 6. Paietta E (1990): Ambigious phenotypes in acute leukemia. Leukemia and Lymphoma 2:17-33. 7. Bardi G, Pandis N, Arsenis P, Stamatellou M, Dermitzaki K, Papanastasiou C, Tsakanikas S, Kallinikou-Maniatis A (1989): Mixed lineage leukemia with cytogenetically urelated abnormal clones. Cancer Genet Cytogenet 40:83-87. 8. Michaeli J, Lerer I, Rachmilewitz EA, Fibach E (1986): Stimulation of proliferation of human myeloid leukemia cells in culture: Application for cytogenetic analysis. Blood 68:790-793. 9. Raimondi S, Ragsdale ST, Behm F, Rivera G, Williams DL (1987): Multiple telomeric associations of a trisomic whole q arm chromosome 1 in a child with acute lymphoblastic leukemia. Cancer Genet Cytogenet 24:87-93. 10. Shinohara T, Nomura T (1988): "Jumping translocation" of a trisomic whole arm of chromosome #1 in an acute lymphoblastic leukemia. Abstract XXII, Congress of International Society of Haematol. 11. Fitzgerald PH, Morris CM (1984): Telomeric association of chromosome in B-cell lymphoid leukemia. Hum Genet 67:385-390. 12. Whang-Peng J, Lee EC, Sieverts H, Magrath T (1984): Burkitt's lymphoma in AIDS: Cytogenetic Study. Blood 63:818-822. 13. Shippey CA, Layton M, Secker-Walker M (1990): Leukemia characterized by multiple subclones with unbalanced translocations involving different telomeric segments: Case report and review of the literature. Genes Chrom Cancer 2:14-17. 14. Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu J-R (1988): A highly conserved repetitive DNA sequence, (TTAGGG)n present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85:6622-6626. 15. Haas OA (1990): Centromeric heterochromatin instability of chromosomes 1,9 and 16 in variable immunodeficiency syndrome--a virus-induced phenomenon? Hum Genet 85:244-246. 16. Morris CM, Fitzgerald PH, Neville MA, Wyld PJ, Beard MEJ (1984): Does multisomy of chromosome l q confer a proliferative advantage in B-cell acute lymphoplastic leukemia? Cancer 54:48-53. 17. Brito-Babapulle U, Atkin NB (1981): Break points in chromosome #1 abnormalities of 218 human neoplasms. Cancer Genet Cytogenet 4:215-225. 18. Cervantes F, Prieto F, Badia L, Orts A (1988): Trisomy of the long arm of chromosome 1 in patients with hematologic malignancies and solid tumors: Report of six cases. Cancer Genet Cytogenet 31:165-170. 19. Najfeld V, Seremetis S, Troy K, Vehlinger J, Schwartz P, Cuttner J (1986): Trisomy 22--A new abnormality found in acute leukemia characterized by eosinophilia and monocytoid blasts expressing immature differentiation antigens. Cancer Genet Cytogenet 23:105-114. 20. Grois N, Nowotny H, Tyl E, Krieger O, Kier P, Haas OH (1989): Is trisomy 22 in acute myeloid leukemia a primary abnormality or only a secondary change associated with inversion 167 Cancer Genet Cytogenet 43:119-129.