Marker Chromosome l q ÷ in Acute Lymphocytic Leukemia

Iskra Petkovit , Melita Nakit , Aleksandar Tiefenbach, Josip Konja, Maja Ka telan, Ljubica Rajit , and Ranka Feminit -Kes

ABSTRACT: This paper presents the results of a cytogenetic analysis on a patient with acute lympho- cytic leukemia (ALL) type L2 according to the FAB classification. Of the metaphases exam- ined, 69.3% belong to the aberrant clone of pseudodiploid karyotype. Marker chromosome 14q+ has been identified in all the cells of the clone. Duplication was found in 30% of the metaphases, and in 15% triplication of the proximal segment of the long arm of chromosome #1 (ql 1-q21). In one metaphase the long arm of chromosome #1 is made up of segment q11- q21 four times repeated. Aberrations of chromosome #1 support the idea that heterochro- matic region may be related to the higher degree of the cell malignity.

INTRODUCTION

Aberrations of chromosome #1 frequently accompany malignant transformation. They have been found in both malignant hemopathies and in solid tumors in hu- mans [1-8]. This wide range of human neoplasms with chromosome #1 aberrations suggests that they are not a primary disorder in the process of malignant transfor- mation, but are probably of secondary in nature and appear in the course of clonal evolution [6, 9-11].

This report presents a case of lymphocytic leukemia with tandem duplication and triplication of the proximal segment of the long arm of chromosome #1, which appeared in the course of clonal evolution.

MATERIALS AND METHODS

Cytogenetic analysis of malignant cells was carried out immediately after the diag- nosis had been made and before initiating therapy. Preparations obtained after 24- hour peripheral blood cell culture without mitogen stimulation were used. Chro- mosome identification was made by applying GTG and BCG bending methods. Be- sides the cytogenetic analysis of the malignant cell population, determination of the patient's constitutional karyotype was also carried out on a routine lymphocyte culture method stimulated with PHA.

From the Institute for Mother and Child Health (I. P., M. N.), the Division of Hematology and Oncology ~alata, Department of Pediatrics, Faculty of Medicine (A. T., J. K., L. R., R. F-K.), and the Department of Oncology and Radiotherapy, Medical Faculty (M. K.), University of Zagreb, Zagreb, Yugoslavia.

Address requests for reprints to Dr. Iskra Petkovi~, Svearova 5, 41000 Zagreb, Yugoslavia. Received December 2, 1985; accepted February 18, 1986.

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© 1987 Elsevier Science Publishing Co., Inc. Cancer Genet Cytogenet 24:251-255(1987) 52 Vanderbilt Ave., New York, NY 10017 0165-4608/87/$03.50

252 I. Petkovid et al.

CASE HISTORY

The patient was a 14.5-year-old boy admitted to the hospital for poor general health, exhaustion, edema of the eyelids, weight loss, pain in the knees and below the rib arches, and enlarged liver, spleen, and lymph nodes. On admission the number of leukocytes in the peripheral blood was 6.2 x 109/L with 0.12 lymphoblasts. In the bone marrow 90% of the cells were found to fulfill the criteria of L2 lymphoblasts, according to the FAB classification. Other lines of hematopoiesis were almost com- pletely repressed and there was no thrombocytopoiesis. Cytochemical investiga- tions showed that the cells were periodic acid-Schiff, peroxidase, and esterase neg- ative, but acid phosphatase was positive. High-risk group anti-leukemia therapy was given. After 3.5 months the boy was in good condition in complete hematologic

Figure 1 G-banded karyotype of a leukemic cell: 46,XY,trip (1)(qllq21),14q +.

1 2 3 4 5

i{ i} i( 1| ii C! Ii 6 7 8 9 10 11 12

II !i It ¢i il N 13 14 15 16 17 18

i i ell ~ ie, ~e 19 20 21 22 X y

Marker l q + in ANLL 253

Figure 2 Partial karyotypes of G-banded leukemic cells show- ing duplication (A), triplication (B), and quadruplication (C) of bands q l l to q21 on chromo- some #1. A normal chromo- some #1 is on the left side in each pair.

remission and was discharged from hospital. He was readmitted shortly thereafter, however, in a deteriorated condit ion with a profound pancytopenia. The clinical condit ion of the patient did not improve with a fast lethal outcome of the disease.

RESULTS AND DISCUSSION

Cytogenetic investigation on a lymphocyte culture stimulated by PHA revealed a normal consti tut ional karyotype. The modal number of malignant cell chromo- somes was 46. A total of 41 metaphases was analyzed. Twelve cells (30.7%) had a normal karyotype, whereas, 69.3% of the metaphases belonged to an aberrant clone with a pseudodiploid karyotype. GTG banding methods revealed a structural dis- order of chromosomes #1 and #14. A marker chromosome, 14q+, was present in all cells of the clone, whereas, in eight metaphases (20.5%) this was the only chro- mosome disorder. It was not possible to determine the origin of the excess material on chromosome #14 (Fig. 1). Aside from chromosome 14q+, a structural anomaly of chromosome #1 was also found in 19 cells. By precise analysis of the band pattern of the long arm of the aberrant chromosome, duplicat ion was identified in some cells and in others triplication of the 1q11-q21 segment (Fig. 2). The proximal segment of the long arm of chromosome #1 (i.e., a segment of the constitutive heterochromatin] was affected by dupl icat ion of triplication, which was confirmed with a BCG banding method (Fig. 3). Duplication was found in 12 (30.7%) and triplication in six metaphases (15.3%) examined. In one metaphase an aberrant chromosome #1 with an interesting G-banding pattern was identified, It seems that the long marker arm was made up of the 1q11-q21 segment repeated four times,

254 I. Petkovi~ et al.

Figure 3 Partial karyotype of three C-banded malignant cells (duplication A, triplication A).

V

whereas, the distal part of the long arm (1q21-qter) was lost. Two metaphases had a tetraploid number of chromosomes but, due to the poor quality of the metaphases, they could not be karyotyped.

Only two descriptions of tandem triplications of the long arm of chromosome #1 have been found in the literature. Papenhausen et al. and Knuut i la et al. have identified tandem triplication q21-q32 in the case of myelodysplastic syndrome and essential thrombocythemia, respectively [12, 13]. In our case of ALL-- in addition to the marker 14q + - -dup l i ca t ion , triplication, and quadrupl icat ion of a segment of the long arm of chromosome #1, ranging from band q l l to q21, has been estab- lished. Marker chromosome distr ibution in the malignant cell populat ion indicated instability and a gradual accumulat ion and higher complexity of structural chro- mosome aberrations. Chromosome dup(1) is unstable and prone to further changes, which is indicated by the existence of a marker with segment triplication or a marker where the segment is repeated four times. The mechanism responsible for mult ipl icat ion may be that suggested by Pall [14]. It is of interest that the region of chromosome #1 involved in the mult ipl icat ion comprised the segment of consti- tutive heterochromatin. Doneda et al. suggested that e l iminat ion or relocation of heterochromatic regions may favor tumor progression [15]. Thus, the finding su- ports the idea that heterochromatic region may favor a higher degree of malignancy.

Supported by Grant 59 from Samoupravna interesna zajednica za znanstveni rad u oblasti zdravstva SR Hrvatske, Yugoslavia.

The authors thank Dr. N. B. Atkin (Mount Vernon Hospital, Northwood, England) for his useful suggestions.

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