SHORT COMMUNICATION

Critical Chromosome Rearrangement in Acute Promyelocytic Leukemia

Sakari Knuutila, Tapani Ruutu, Riitta Kovanen, Marja Ekblom, and Albert de la Chapelle

ABSTRACT: We report here a patient with acute promyelocytic leukemia (APL) who has two normal chromosomes #15 but a structurally abnormal chromosome #17. This case indicates that the critical point of rearrangement in APL is not necessarily in chromosome #15 but may, alter- natively, be in chromosome #17.

A specific t ranslocat ion between chromosomes #15 and # 1 7 occurs in at least 40%-60% of pat ients wi th acute promyelocyt ic leukemia (APL) [1-3]. Complex translocat ions have also been observed and have so far indica ted that chromosome #15 is always abnormal [4, 5]. We report here a pat ient wi th APL in first re lapse who has two normal chromosomes #15 but a s t ructural ly abnormal chromosome #17.

The pat ient was a 58-yr-old woman who presented in Apr i l 1982 with fatigue and nasal bleeding. There were no abnormal findings on physical examinat ion. He- moglobin concentrat ion was 106 g/L, leukocyte count 119 x 109/L, and pla te le t count 90 x 109/L. Differential count of per iphera l blood leukocytes showed 77% leukemic cells. Bone marrow aspirate showed markedly increased cellulari ty. Sixty- five percent of the cells were pr imi t ive abnormal cells (Fig.l). The nucleus of most of these was k idney-shaped , bi lobed, or mul t i lobula ted and showed up to three nucleoli . The majori ty of the cells contained high numbers of fine faintly orange- staining granules in their cy toplasm (May-Gr i inwa ld -Giemsa staining). Many cells were packed wi th these granules. A few cells had large red to purple granules, but they were not abundant in number. Auer rods were found, but their number was low, and no "faggot cel ls" were seen. The ethanol gelat ion test was posi t ive and fibrinogen degradat ion products were found, indica t ing d issemina ted int ravascular coagulation. Acute myelo id leukemia (AML) was diagnosed. According to the FAB- classification [6] this case was thought to represent a variant form of M3.

The pat ient was treated with the TAD combinat ion [7] and after two courses achieved remission. She then received as consol idat ion a further course of TAD, a combinat ion of cytarabine, e toposide, cyc lophosphamide and vincris t ine, and a course of high-dose methotrexate at month ly intervals, but re lapsed in September 1982. The morphology of the leukemic cells at that t ime was s imilar to that at diagnosis.

From the Department of Medical Genetics and Third Department of Medicine, University of Helsinki, Finland.

Address requests for reprints to Dr. Sakari Knuutila, Department of Medical Genetics, Uni- versity of Helsinki, Haartmaninkatu 3, 00290 Helsinki 29, Finland.

Received April 11, 1983; accepted June 25, 1983.

473

© 1984 by Elsevier Science Publishing Co., Inc. Cancer Genetics and Cytogenetics 11, 473477 (1984) 52 Vanderbilt Ave., New York, NY 10017 0165-4608/84/$03.00

474 s. Knuut i la et al.

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Figure 1 Bone marrow aspirate at presentation.

The first chromosome study was performed on bone marrow cells by a direct method [8] at the time of diagnosis, All 24 mitoses studied were cytogenetically normal; retrospective reevaluation of the same cells failed to disclose any abnor- mality. The patient was restudied at relapse, 5 mo after diagnosis, and 6 out of 71 mitoses in bone marrow preparations made by the same direct method showed a minor structural abnormali ty of one chromosome #17 (Figs. 2 and 3). It is possible that the abnormal chromosome #17 already existed at the time of diagnosis but as most of tile mitoses studied contained chromosomes with fewer than 300 bands per haploid set, it may have been missed because it was submicroscopic in low reso-

lution banding. The abnormali ty was not easily detectable. Both chromosomes #15 were normal

as were all the other chromosomes, The structurally abnormal #17 was the same size as its normal homologue or only slightly shorter than it. The dark portion of the distal part of the long arm (normally consisting of bands q22 to q24) was shorter than normal, whereas the light central band q21 was longer than normal. This is compatible with the toss of either band q22 or q24 and its reptacemmrt with lightly staining material. A paracentric inversion with break points in the proximal and distal parts of the long arm may have contributed to but does not fully account for the abnormality.

We conclude that the critical point of rearrangement in APL is not necessarily in chromosome #15 but may, alternatively, be in chromosome #17.

This work was supported by grants from the Finnish Cancer Society, the Sigrid Jus61ius Foun- dation, and the Nordisk Insulinfond.

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Crit ical C h r o m o s o m e R e a r r a n g e m e n t in APL 477

REFERENCES

1. First International Workshop on Chromosomes in Leukaemia (1978): Chromosomes in acute nonlymphocytic leukaemia. Br J Haematol 39:311-316,

2. Second International Workshop on Chromosomes in Leukemia (1980): Chromosomes in acute promyelocytic leukemia. Cancer Genet Cytogenet 2:103-107.

3. Fourth International Workshop on Chromosomes in Leukaemia {1983): (in preparation)

4. Rowley JD (1982): Identification of the constant chromosome regions involved in human hematologic malignant disease. Science 216:749-751.

5. Rowley ID (1983): Human oncogene locations and chromosome aberrations. Nature 301:290-291.

6. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (FAB Co-operative Group)(1980): A variant form of hypergranular promyelocytic leukaemia (M3). Br J Haematol 44:169-170.

7. Gale RP, Cline MJ (1977): High remission-induction rate in acute myeloid leukaemia. Lan- cet 1:497-499.

8. Knuutila S, Vuopio P, Etonen E, Slimes M, Kovanen R, Borgstr6m GH, de la Chapelle A (1981): Culture of bone marrow reveals more cells with chromosomal abnormalities than the direct method in patients with hematologic disorders. Blood 58:369-375.

ADDENDUM

D u r i n g t he ed i to r i a l h a n d l i n g of the p r e s e n t p a p e r Y a m a d a et al. h a v e also con- c l u d e d t ha t c h r o m o s o m e #17 is c ruc i a l l y i m p o r t a n t in the p a t h o g e n e s i s of APL (Cancer Genet Cytogenet 9:93, 1983). F u r t h e r m o r e , we h a v e f o u n d a n o t h e r APL case tha t has two n o r m a l c h r o m o s o m e s # 1 5 bu t a s t r u c t u r a l l y a b n o r m a l # 1 7 .