12q13, A new recurrent breakpoint in acute non-lymphoblastic leukemia

ELSEVIER

12q13, A New Recurrent Breakpoint in Acute Non-Lymphoblastic Leukemia Marieke M. B. Seyger, Jutta Ritterbach, Ursula Creutzig, Astrid K. Gnekow, Ulrich GObel, Norbert Graf, Alfred Reiter, Fritz Lampert, and Jochen Harbott

ABSTRACT: The kary•types •f 312 successfu••y ana•yzed samp•es •f chi•dren with acute n•n-•ymph•b•astic

leukemia (ANLL), which were sent to us by 72 German hospitals, were e x a m i n e d in order to find new recurrent chromosome abnormalities of possible clinical relevance. Whereas most of the patients had one of the specific aberrations of ANLL or a n o r m a l karyotype, random numerical or structural changes were found in 61 children (20%). Four of them showed an abnormality involving band 12q13: t(12;17) (q13;q21), t(12;21) (q13;q21), t(2;12) (p13;q13), and t(5;12) (pll;q13). Despite the fact that FAB subtypes were different (MO, M1 M6, AHL), the blasts of all patients were characterized by immaturity and were difficult to classify. The breakpoint 12q13 might be of clinical importance in ANLL, because the four patients in our study, as well as the 21 patients with this aberration found in the literature, had a very p o o r prognosis.

INTRODUCTION Cytogenetic analysis using b a n d i n g techniques has been increasingly a p p l i e d to the study of m a l i g n a n t diseases in recent years. Especially in acute leukemias these investigations became m o r e and more important, because of the diagnostic, prognostic, and therapeutic value of the c h r o m o s o m a l findings [1-6]. Up to now, several consistent c h r o m o s o m a l aberrations were found, w h i c h are very often closely associated with specific i m m u n o p h e n o t y p e s of ALL or FABsubtypes of ANLL, e.g., t(9;22) in c-ALL, t(4;11) in p r e pre-B-ALL, t(8;14) in B-ALL, t8;21) in ANLL-M2, t(15;17) in ANLL-M3, or t(9;11) in ANLL-M5 [7, 8]. A b o u t 20-30% of the c h r o m o s o m a l changes in ALL and ANLL found in leukemic cells, however, were described to be r a n d o m aberrations [9-12]. Very often these anomalies were only found in one or two patients a n d have no correlation to clinical parameters. By the rising n u m b e r of cytogenetic analyses, however, aberrations formerly regarded to be random were recently described

From the Oncacytogenetic Laboratory, Children's Hospital, University of GieJ~en (M.M.B.S., ].R., EL., J.H.); Children's Hospital, University of MfJnster (U.C.); Children's Hospital, University of Saarbriicken, Homburg/Saar (N.G.); Children's Hospital, KZV Augsburg (A.K.G.); Children's Hospital, Medical School of Hannover (A.R.); Children's Hospital, University of Dfisseldorf, Germany (U.G.). Address reprint requests to: Dr. ]ochen Harbott, Oncogenetic Laboratory, Children's Hospital, University of GieJ]en, Feulgenstrasse 12, D-35383 Gief~en, Germany. Received April 21, 1994; accepted July 25, 1994. Cancer Genet Cytogenet 80:23-28 (1995) © Elsevier Science Inc., 1995 655 Avenue of the Americas. New York, NY 10010

as rare but very typical abnormalities, closely related to specific clinical parameters [13-16]. In the present study we therefore checked c h r o m o s o m a l aberrations of children with ANLL, collected during a period of 10 years in the Oncogenetic Laboratory at Giet~en and originally classified as random, to find patients with corresponding chromosomal abnormalities and similar clinical features. MATERIALS AND METHODS

Bone marrow and b l o o d samples, w h i c h arrived m a i n l y by mail (90-95%), were prepared directly or incubated in RPMI 1640 + 20% fetal calf s e r u m (FCS) and c u l t u r e d for 24 or 48 h. The cell s u s p e n s i o n was then brought to hypotonic solution (KC1, 15 minutes) and fixed in methanol-acetic acid (3:1). After being washed, the cells were d r o p p e d onto a cold wet slide to spread the metaphases. G-banding was performed after a t r y p s i n pretreatment (10-15 sec) 3-5 days later. Classification of c h r o m o s o m a l breakpoints was done according to the ISCN [17, 18] and Third International Workshop on Chromosomes in Leukemia [1]. RESULTS

From January 1984 to December 1993 bone marrow or blood of 422 c h i l d r e n w i t h acute n o n - l y m p h o b l a s t i c leukemia (ANLL) were investigated cytogenetically, and 312 (74%) samples could be analyzed successfully. Whereas 89 (28%) of these c h i l d r e n showed a completely normal karyotype, 162 (52%) patients had one of the follow-

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ing specific aberrations: t(8;21), t(15;17), t(9;11), der(11)(q23), inv(16), der(3q), +4, + 8, - 5 / 5 q - , and - 7 / 7 q - . The other 61 (20%) patients h a d other clonal aberrations w h i c h were classified as random. With the exception of c h r o m o s o m e s 18 and Y, all c h r o m o s o m e s were involved in these numerical or structural changes. A m o n g them, four translocations were detected w i t h a b r e a k p o i n t in 12q13: t(12 ;17)(q13 ;q21), t(12;21)(q13;q21), t(2;12)(p12;q13), and t(5;12)(p11;q13). This breakpoint, however, was not found in the bone marrow of 877 c h i l d r e n w i t h ALL at diagnosis w h i c h was successfully analyzed in our laboratory in the same period. All four child r e n showed a type of acute leukemia w i t h a high amount of immature blast cells that was therefore difficult to classify. The clinical data and laboratory features of these four patients are described in detail below and s u m m a r i z e d in Table 1. CASE REPORTS Patient 1

A 3.5-year-old girl w i t h Down s y n d r o m e had a 2-week history of respiratory infection, fatigue, weakness, and remarkable petechiae. She presented w i t h pallor, hematomas, petechiae, adenopathy, and hepatosplenomegaly. Her leukocyte count was 36.3 × 109/L with 18% lymphocytes, 5% normoblasts, a n d 49% undifferentiated cells. Hem o g l o b i n was 7.3 g/dL, thrombocytes were 35 × 109/L, respectively. There were 58% undifferentiated immature cells in the bone marrow, resembling erythroblasts, together with dyserythropoetic cells and lymphocytes. The cytochemical staining was positive for PAS reaction in some blasts only a n d i m m u n o p h e n o t y p i n g was positive for the myelomonocytic antige.ns VIM D5 a n d MY 806. TEIT was negative and a slight crossreaction w i t h pan-T antigens was found. It was therefore diagnosed as erythroleukemia (FAB-M6) or unclassifiable leukemia (AUL). The leukemic blast karyotype, w h i c h c o u l d be detected in 18/22 (82 %) of the metaphases, was 47,XX,t(2 ;12)(p13;q13), + 21c (Fig. la), whereas the remaining four metaphases showed no acquired chromosomal aberrations. Table 1

Seyger et al.

Because of the poor prognosis of the child with Downs S y n d r o m e a less intensive therapy w i t h r e d u c e d dosages (consolidation of study AML-BFM-83) was started [19]. During therapy, however, she acquired fever, interstitial pneumonia, and paralytic ileus. After cerebral thrombosis she died in aplasia 2 months after diagnosis. Patient 2

A 3-year-old boy presented with fever and hematomas in poor clinical condition, after a 3-month history of pallor and fever. Adenopathy and h e p a t o s p l e n o m e g a l y were present. The leukocyte count was 25.8 x 109/L with 93% undifferentiated blasts, 3% normoblasts, and 4% lymphocytes. H e m o g l o b i n was 7.2 g/dL and the thrombocyte count was 36 × 109/L. Bone marrow blasts showed slight maturation, granules, and a positive peroxydase reaction in 90% of them. Because other cytochemical stainings could not be performed a n d myelomonocytic antigens (VIM-D5 and MY 7) were expressed, FAB classification of M1 was made with some restrictions. The karyotype 46,XY,t(12;21)(q13;q21) (Fig. lb) was detected in 20/22 metaphases (91%), whereas a normal karyotype was only found twice. The patient was treated initially with ara-C, daunorubicin, and etoposide for 8 days, according to the protocol of the G e r m a n therapy study AML-BFM-83 [19]. After severe bone marrow depression, start of consolidation therapy with seven different drugs and cranial irradiation was delayed. The patient d i e d of infection 2 weeks after allogeneic bone marrow transplantation (BMT), which was performed in partial remission 1 year after diagnosis. Patient 3

A 1.5-year-old girl presented with leukemic infiltration of the paranasal sinuses, orbitae, and the soft tissue of both jaws. Her leukocyte count was 23.8 × 109/L, with 23% blasts w i t h large vacuoles. H e m o g l o b i n was 8.4 g/dL and thrombocyte count was 27 × 109/L. Blasts in the bone marrow were large, undifferentiated, without granules but with cytoplasma blebs, containing PAS-positive granula. Peroxi-

Clinical data of the patients of this study with 12q13 aberrations

Age (years) Sex Leucocyte count (~L) Platelet count (#L) Hemoglobin (g/dL) Blasts in BM (%) Blasts granulated Peroxydase reaction Liver (cm) b Spleen (cm) b FAB type Remission status Survival (months)

N.T. (2}a

S.K. (23)

A.W. (15)

B.K. (5)

3.7 F 36,300 35,000 7.3 58% Yes Negative 4 7 M6 PR 2

3.0 M 25,800 36,000 7.2 81% Yes Positive 3 1 M1 PR 12

1.4 F 23,800 27,000 8.4 89% No Negative 3 0 M0 ED 1

10.5 M 4,800 42,000 8.3 87% Yes Positive 4 12 AHL CR (late) 27 + (BMT)

PR, partial remission; ED, early death; CR, complete remission; BMT, bone marrow transplantation. a Number in parentheses corresponds to patient number in Table 2. b Below costal margin. Abbreviations:

12q13 Aberrations in ANLL

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a)

,p-

!

t

.........

b)

differentiated blasts. The h e m o g l o b i n was 8.3 g/dL and the thrombocyte count was 42 x 109/L. In the bone marrow smears 86% m a i n l y undifferentiated heterogeneous blasts with some peroxidase-negative granules were found and the cytochemical stainings were positive for PAS reaction in only 3% of the blasts. Immunophenotyping showed expression of an early myeloid antigen (CD33) and of the T-cell antigens CD3 and CD7. CD34 was distinctly positive (62%). The leukemia was classified as acute hybrid leukemia (AHL) and the patient was treated according to study ALLBFM-90, with therapy-free intervals due to hepatic problems. Response to treatment was delayed, with persisting blasts in the p e r i p h e r a l b l o o d over 3 weeks. Now, after allogeneic BMT, the boy is in remission for more than 2 years. Thirty-six metaphases were analyzed, and besides three with a normal karyotype, 92 % with the following aberrations were detected: 46,XX,der(3p),t(5;12)(p11;q13),der(6q),der(7q). DISCUSSION

c)

i

I

d) F i g u r e 1 Partial karyotypes of four children with 12q13 aberrations: a) t(2;12)(p13;q13), b) t(12;21)(q13;q21), c) t(12;17)(q13;q21), and d) t(5;12)(p11;q13). Normal chromosomes are shown on the left and on the right of the abnormal ones.

dase reaction was negative. Myeloid i m m u n o l o g i c markers (CD 33) were positive, allowing the diagnosis of FAB-MO. In the majority of the cells (10/12) the karyotype was 47,XX, + der(10)t(1;10) (q25 ;q22),t(12 ;17)(q13 ;q21) (Fig. lc), and two metaphases were normal. During i n d u c t i o n therapy consisting of era-C, daunorubicin, and etoposide, she acquired fever, enteritis, and epidermolysis. She died 3 weeks after diagnosis in aplasia with progressive renal failure. Patient 4

A 10.5-year-old boy presented w i t h cholestatic icterus and hepatic failure (thromboplastin time <20%). Liver and spleen were enlarged (4 and 12 cm, respectively, below costal margin). The leukocyte count was 4.8 × 109/L, w i t h 87% nn-

Whereas most of the chromosomal changes in leukemic cells are typical for one of the i m m u n o l o g i c subgroups of ALL or the FAB types of ANLL, respectively, about 20% of t h e m appear randomly. Most of t h e m are found only once, but some were detected in more then one patient [5, 20, 21]. The clinical parameters of these c h i l d r e n were c o m p a r e d to define a new entity of specific abnormalities. Structural abnormalities of chromosome 12 in acute leukemia are well-known. Most frequently, however, the break occurs in the short arm [21-23]. 12q13 as a breakpoint in ANLL has up to now been reported in 25 patients, including those in this study. Most of the authors describe only one patient (Table 2), a n d one can assume that this is a very rare type of aberration. Nearly all abnormalities of c h r o m o s o m e 12q13 are translocations, excluding one deletion and one duplication. Eleven different chromosomes were found to be involved in translocations, and the most frequent partners were the chromosomes 17 (n = 4), 19 (n = 4), 7 (n = 3), and 11 (n = 3). Whereas in chromosomes 7, 11, and 17 the breakpoints differed, the band p13 in c h r o m o s o m e 19 was involved in all patients. The same region is often found as a breakpoint in other translocations [t(1;19); t(11;19)]. The band 12q13, w h i c h is very closely correlated not only to liposarcomas [21, 24, 25] but also to other solid tumors [26-30], is also k n o w n as a heritable fragile site [31-33] and three oncogenes are m a p p e d in this region: int-1, gli, and ERB-B3 [5, 34]. Whereas all ANLL patients with 12q13 aberrations described so far had additional numerical or structural abnormalities, two of the children in this study had no other acquired aberrations (patients 1, 2). Patient 1, however, showed a constitutional trisomy 21. Most of the children had complex karyotypes with multiple rearrangements; a single additional change was found in only six. Fourchildren showed two different clones in the leukemic ceils. As to the type of leukemia, it could be shown that with one exception [35] all patients had acute myelogenous]eukemias, which were, however, classified to different FAB sub-

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Table 2

C l i n i c a l d a t a of p a t i e n t s w i t h 12q13 a b e r r a t i o n s ( C o m p a r i s o n of t h e literature)

Patient No.

12q13 aberration

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

t(1,12)(p36;q13) t(2;12)(p13;q13) t(3;12)(p14;q13) c (t4;12)(q13;q13) t(5;12)(p11;q13) t(7;12)(q11;q13) t(7;12)(q21;q13) t(7;12)(q21;q13) t(8;12)(q22;q13) t(11;12)(p14;q13) c t(11;12)(q25;q13) t(11;12)(p11;q13) t(12;16)(q13;q24) t(12;16)(q13;q24) t(12;17)(q13;q21) t(12;17)(q13;p12) c t(12;17)(q13;p11) c t(12;17)(q13;p12) t(12;19)(q13;p13) t(12;19)(q13;q13) t(12;19)(q13;q13) t(12;19)(q13;q13) t(12;21)(q13;q21) del(12)(q12q14) dup(12)(q13q24)

Additional aberrations + + + + + + + + ÷ + + + + + + + + + + + +

S e y g e r et al.

Sex

Age (years)

Time of examination a

FAB

Remission status b

Survival (months)

Reference no.

M F F F M M M F M F F M M M F M F F M F M M M M F

22 3.7 57 74 10.5 52 4 58 60 19 60 7 0.5 (16 1.4 64 73 61 58 61 63 63 3 59 3

R D D D D D D D D D D D D D D D D D D D D R D D D

M5a M6 M2 M1 AHL M1/M2 M1 M2 MDS M1/M2 M1 M2 M5 M5 M0 M1/M2 M4 M6 M4 M2 M1 M2 M1 M3 M5a

NR PR NR NA CR(late) NA NA NA NA NR NA CR CR NA NR NR NA NA NR NR NR PR PR NR NR

8.5 2 5 NA 27 + NA NA 3 12 2 3 14.4 18 NA 1 1 2 NA 12 2 1 28 12 2 3 weeks

[36] This report [37] [38] This report [39] [40] [41] [42] [43] [44] [45] [46] [10] This report [47] [48] [49] [50] [23] [23] [23] This report [51] [52]

o D, at diagnosis; R, at relapse. b Cr, complete remission; PR, partial remission; NR, no remission; NA, not available. c Secondary ANLL.

t y p e s . M o s t f r e q u e n t l y (n : 13) ANLL-M1/M2 w a s f o u n d , w h e r e a s o t h e r s u b t y p e s a p p e a r e d o n l y r a r e l y (1-3 t i m e s ; Table 2). S m e a r s of t h e p a t i e n t s of t h i s s t u d y w e r e r e v i e w e d by t h e M o r p h o l o g y P a n e l of t h e West G e r m a n A M L - B F M s t u d i e s * a n d w e r e r e p o r t e d to b e d i f f i c u l t to c l a s s i f y m o r p h o l o g i c a l l y . T h e blasts w e r e i m m a t u r e i n all four p a t i e n t s a n d classification of FAB - M0, - M1, - M6, a n d AHL, r e s p e c tively, w e r e m a d e . O u t c o m e w a s p o o r i n o u r p a t i e n t s , as w e l l as i n t h o s e r e p o r t e d in t h e l i t e r a t u r e (Table 2). M o s t of t h e m h a d r e s i s tant d i s e a s e or early r e l a p s e s a n d o n l y four p a t i e n t s s u r v i v e d l o n g e r t h a n 1 year. C h r o m o s o m e a b e r r a t i o n s i n v o l v i n g t h e l o n g a r m of c h r o m o s o m e 12 at t h e b a n d s q13 s e e m to b e a rare e n t i t y of aberr a t i o n s i n ANLL, i n d i c a t i n g a d i s o r d e r of early h e m a t o p o e sis. T h e p o o r p r o g n o s i s f o u n d for m o s t of t h e p a t i e n t s m i g h t b e d u e to t h e fact t h a t n e a r l y all k a r y o t y p e s a l r e a d y s h o w e d a c l o n a l e v o l u t i o n at d i a g n o s i s . T h i s p h e n o m e n o n is des c r i b e d as a n i n d i c a t o r of a s t r o n g p r o l i f e r a t i o n of t h e m a l i g n a n t clone. T h e s e f i n d i n g s a n d t h e c o m p a r i s o n w i t h t h e data of t h e literature s h o w t h e c l i n i c a l i m p o r t a n c e of c y t o g e n e t i c results,

* Members of the Morphology Panel were: Prof. Dr. Th. B~ichner, Dr. U. Creutzig, Prof. Dr. W. Hiddemann, Prof. Dr. H. L6ffler, Prof. Dr. J. Ritter, Prof. Dr. G. Schellong, and Prof. Dr. D. Urbanitz.

even if t h e y s e e m to be r a n d o m . Collecting m o r e data of chrom o s o m e a b e r r a t i o n s i n c h i l d r e n a n d a d u l t s w i l l be h e l p f u l i n f i n d i n g f u r t h e r c y t o g e n e t i c s u b g r o u p s of c l i n i c a l i m p o r tance. This study was supported by the "Kind-Philipp-Stiftung" the "Parents' Leukemia Research Fund, Giefien" the "ERASMUS Student's Exchange Program" and the "Forschungshilfe Station Peiper:' For technical assistance we thank Mrs. S. Gr/if-H6chst, A. Jaeckel, and S. S/ifilin. We further thank all colleagues of the German Paediatric Oncologic Centers for supporting us with bone marrow and blood samples.

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12q13 A b e r r a t i o n s in A N L L

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