Acute Promyelocytic Leukemia with a Dicentric Chromosome Involving Chromosomes 11, 17, and 18 Yap-Yee Chong, Gee-Chuan Wong, Lai-Ching Lau, Louise Knight, Ping Lim, Weng-Oon Lui, Min-Hwee Yong, Yeow-Tee Goh, and Patrick Tan
ABSTRACT: We report a case of acute promyelocytic leukemia with dicentric chromosome resulting from translocation of chromosomes 11, 17, and 18. © Elsevier Science Inc., 1998
INTRODUCTION Several nonrandom chromosomal abnormalities have been reported in acute myelogenous leukemia (AML) [1–3]: t(8;21) in AML M2 in the French-American-British (FAB) classification, t(15;17) in AML M3, inv(16) in AML M4Eo. Recently, two rare syndromes of AML M3 or acute promyelocytic leukemia (APL) associated with t(11;17) (7) and t(5;17) were described [4–6]. In this paper, we report a case of AML with morphological and clinical features similar to those of AML M3, with a complex three-way translocation involving chromosomes 11, 17, and 18 resulting in a dicentric chromosome. CASE REPORT The patient was a 25-year-old Chinese man who presented to a hospital in Australia with lethargy, epistaxis, and a petechial rash of 1-week duration. Complete blood count showed hemoglobin of 9.7 g/dL, platelet count of 10 3 109/L, and total white count of 3.5 3 109/L with 21% blasts in the peripheral blood film. A bone marrow aspirate and trephine showed acute myeloid leukemia and was initially classified as M2 in accord with the FAB criteria, although the hematologist thought that some morphologic features of M3 were present. The patient was treated with alltrans-retinoic acid (ATRA) for 1 week followed by induc-
From the Department of Pathology, (Y.-Y. C., L.-C. L., W.-O. L., P. L., L. K., M.-H. Y.) and the Department of Hematology (G.-C. W., Y.-T. G., P. T.), Singapore General Hospital, Singapore, Republic of Singapore. Address reprint requests to: Dr. Yap-Yee Chong, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Republic of Singapore. Received April 2, 1997; accepted October 20, 1997. Cancer Genet Cytogenet 105:69–73 (1998) Elsevier Science Inc., 1998 655 Avenue of the Americas, New York, NY 10010
tion chemotherapy consisting of high-dose Ara-C (HIDAC), 3 g/m2 bd days 1, 3, 5, and 7, Idarubicin 12 mg/m2 days 1, 2, and 3, and Etoposide 75 mg/m2 days 1–7. A bone marrow aspirate and trephine on day 28 showed morphological remission. Consolidation chemotherapy (“525”) consisting of Ara-C 100 mg/m2 days 1–5, Idarubicin 12 mg/m2 day 1 and 2, and Etoposide 75 mg/m2 days 1–5 was administered. A bone marrow on day 29 of consolidation showed 12% blasts. A second cycle of HIDAC was started. The patient was then referred to us for further treatment. A repeat marrow in our hospital showed persistent leukemia (8% blasts). Treatment with Mitoxanthrone and ATRA was started. His sister was found to be a 5 antigen match with mismatch at one HLA A locus. He was transplanted but developed complications of veno-occlusive disease of the liver, graft-versus-host disease of the liver, and septicemia. He died on day 53 post-bone-marrow transplant. MATERIALS AND METHODS Cytogenetic studies were performed on cells from 24-hour unstimulated bone marrow aspirate cell cultures. Chromosomes were banded by using a modification of the trypsinGiemsa banding method of Klinger . Fluorescence in situ hybridization (FISH) was performed with the use of Oncor (Gaithersburg, MD) Coatasome 10, 17, 18, 20, a satellite probes 17 and 18, and microdeletion probes according to the protocol recommended by the manufacturer. RESULTS The bone marrow aspirate and trephine were interpreted by us as a variant of APL (Fig. 1). The atypical cells constitute 89% of the nucleated cells, with 33% being blasts with one to three prominent nucleoli and minimal cytoplasmic granules and 56% being abnormal promyelocytes
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Y.-Y. Chong et al.
Bone marrow aspirate showing blasts and atypical promyelocytes similar to those seen in APL. MayGrunwald 3100.
with very prominent cytoplasmic granulation similar to those seen in classical APL except that faggot cells were less prominent. Flow cytometry showed that the blasts expressed CD15 and CD33, but only 30% expressed HLA-DR. They were negative for CD13 and CD34.
CYTOGENETIC EXAMINATION A complex karyotype was observed. The most striking feature is a dicentric chromosome resulting from a complex translocation between chromosomes 11, 17, and 18. In addition, one derivative 10 resulting from a translocation (10;20) (q23;q11.2) and one derivative 11 resulting from a translocation (17;20)(q24;q11.2) were present (Fig. 2). This translocation was determined by FISH as follows (Fig. 3A–H): D18Z1 probe showed that the centromere of chromosome 18 is present on the large derivative. D17Z1 probe showed that the centromere of chromosome 17 also is present on the large derivative. This derivative will now be referred to as dicentric. Paint 17 revealed that most of chromosome 17 is translocated to the middle of the dicentric chromosome and a small part of the long arm is translocated to chromosome 20. Paint 18 revealed that all of chromosome 18 is translocated to the dicentric chromosome. Paint 10 revealed that part of chromosome 10 is translocated to the small derivative. Paint 20 showed that part of chromosome 20 is translocated to chromosome 10.
To determine the breakpoints on chromosome 17, we used two probes intended for the detection of microdeletion syndromes. They are D17S29 Smith-Magenis chromosome region at 17p11.2 and D17S379 Miller-Dieker region at p13.3. Both are supplied with a control probe in the RARA region at 17q21.1. With D17S29, both signals were present on the dicentric chromosome, which means that the breakpoint on the short arm is above 17p11.2 and that it is below 17q21.1 on the long arm. With D17S379, only one signal was present on the dicentric chromosome, which means that the breakpoint on the short arm is below p13.3. We concluded that the breakpoints on chromosome 17 are between p11.2 and p13.3 on the short arm and below the RARA gene on the long arm (Fig. 4). The karyotype of the main-line clone is 45,XY,der(10)t(10;20)(10pter→10q23:: 20q11.2→20qter),dic(11;17;18)(18qter→18p11::17p12→ 17q 24::11q13→11qter),der(11)t(10;11)(11pter→11q13::11q13:: 10q23→10qter),der(20)t(17;20)(20pter→20q11.2::17q24→ 17qter). DISCUSSION APL is consistently associated with a reciprocal translocation, first considered t(15;17)(q21;q11–q21) and now designated t(15;17)(q22;q12) [8, 9]. The translocation results in the fusion of the RARA gene to the PML gene . APL with cytogenetic abnormalities other than t(15;17) do occur but are rare [4–6]. In t(11;17), a new fusion gene was created by linking the gene encoding retinoic acid receptor A (RARA) to a gene encoding a protein with nine zinc-finger motifs named PLZF (promyelocytic leukemia zinc finger) . All of the cases were found to have cytologic fea-
APL with a Dicentric Chromosome
Figure 2 Complex karyotype showing (A) dicentric chromosome, (B) derivative 10, (C) derivative 11, and (D) derivative 20.
tures intermediate between M2 and classical M3 AML. In contrast with the typical AML M3 associated with t(15;17), these cases did not respond to initial conventional chemotherapy or ATRA and had distinctly worse prognoses. In the single case of t(5;17), the translocation fuses the gene for the nucleolar phosphoprotein nucleophosmin (NPM) to RARA . This patient also responded poorly to ATRA. The karyotype of our patient showed a dicentric chromosome involving a three-way translocation of chromosomes 11, 17, and 18. The RARA gene on chromosome 17 and the PLZF gene on chromosome 11 are present in the dicentric chromosome, although they are not fused. The morphology of the abnormal cells and the flow cytometry results lend support to our diagnosis of APL. The absence of CD34, the acquisition of CD15, and the decrease in HLA-DR density are features of further differentiation into neutrophil [11, 12]. The lack of reactivity of HLA-DR antibodies in the majority of APLs is consistent with observations that the normal promyelocyte is HLA-DR negative . Our patient did not respond well to ATRA and aggres-
sive myeloablative therapy. This poor response to ATRA may be an additional characteristic associated with nonclassical translocations in APL. This work was supported by a research grant from the Department of Clinical Research, Singapore.
REFERENCES 1. Rowley JD (1982): Identification of the constant chromosome regions involved in human hematologic malignant disease. Science 216:749–751. 2. Yunis JJ (1983): The chromosomal basis of human neoplasia. Science 221:227–236. 3. Mitelman F (1990): Catalog of Chromosome Aberrations in Cancer. Wiley-Liss, New York. 4. Chen SJ, Zelent A, Tong JH, Yu HQ, Wang ZY, Derre J, Berger R, Waxman S, Chen Z (1993): Rearrangements of the retinoic acid receptor alpha and promyelocytic leukemia zinc finger genes resulting from t(11;17)(q23;q21) in a patient with acute promyelocytic leukemia. J Clin Invest 91:2260–2267. 5. Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR,
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Figure 3 FISH with the use of (A) D18Z1, (B) D17Z1, (C) paint 17, (D) paint 18, (E) paint 10, (F) paint 20, (G) D17S29 probe, and (H) D17S379 probe.
APL with a Dicentric Chromosome
Figure 4 Diagrammatic representation of the dicentric chromosome.
Michaux JL, Wu Y, DeBlassio A, Miller WHJ, Zelenetz AD, Willman CL, Chen Z, Chen SJ, Zelent A, Macintyre E, Veil A, Cortes J, Kantarjian H, Waxman S (1995): Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85:1083–1094. 6. Corey SJ, Locker J, Oliveri D, Shekhter-Levin S, Redner RL, Penchansky L, Gollin SM (1994): A nonclassical translocation involving 17q12 (retinoic acid receptor A) in acute promyelocytic (APML) with atypical features. Leukemia 8:1350– 1353.
9. Larson RA, Kondo K, Vardiman JW, Butler AE, Golomb HM, Rowley JD (1984): Evidence for a t(15;17) translocation in every patient with acute promyelocytic leukemia. Am J Med 76:827–841. 10. Goddard AD, Borrow J, Freemont PS, Solomon E (1991): Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 254:1371–1374. 11. Griffin JD, Linch D, Sabbath K (1983): Surface marker analysis of acute myeloblastic leukemia: identification of differentiation-associated phenotypes. Blood 62:557–563.
7. Klinger HP (1972): Rapid processing of primary embryonic tissue for chromosome banding pattern analysis. Cytogenet Cell Genet 11:424–455.
12. van der Reijden HJ, van Rhene DJ, Lansdorp PM (1983): A comparison of surface marker analysis and FAB classification in acute myeloid leukemia. Blood 61:443–448.
8. Rowley JD, Golomb HM, Dougherty C (1977): 15/17 translocation: a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1:549–550.
13. Terstappen LW, Loken MR (1990): Myeloid differentiation in normal bone marrow and acute myeloid leukemia assessed by multi-dimensional flow cytometry. Anal Cell Pathol 2:229–240.