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Extra Y Chromosome in T-cell Acute Lymphoblastic Leukemia

Ayako Watanabe, Yasunori Kawachi, Toshio Nishihara, Tatsumi Uchida, Kojun Setsu, and Kazumasa Hikiji

ABSTRACT: We describe a 66-year-old man who developed T-cell acute lymphoblastic leukemia (ALL) with a sole chmal chromosomal abnormality of 47,XY,+ Y. Leukemic cells were positive for CD2, CD7, terminal deoxvnucleotidyl transferase and cytoplasmic CD3. T-cell receptor [3, 31, and ~ genes remained germline configurations. The bone marrow aspirate was 47,XY,+ Y in all metaphase cells observed, The patient ach&ved complete remission by chemotherapy, and the bone marrow cells and the phytohemag- glutinin stimulated peripheral blood lymphocytes showed a normal karyotype of 46,XY at that time. This fact sug~:ests that an extra Y chromosome may be a kind of new chromosomal abnormality of T-cell ALL.

INTRODUCTION

A loss of the Y chromosome in patients with leukemia is not rare, which has been suggested as a nonrandom associ- ation [1] or a normal age-related phenomenon without a pathogenetic significance [2]. Or, this phenomenon has also been suggested as a neoplastic change because a loss of the Y chromosome was restored during complete remis- sion in acute myeloblastic leukemia (AML) patients [3]. An extra Y chromosome as the sole clonal change in leu- kemia is very uncommon, and has been described in only three AMLs [4, 5, 6], two B-cell chronic leukemias [7] and one refractory anemia with excess of blasts in transforma- tion (RAEB-T) [8]. We report a rare case of a 66-year-old normal 46,XY man who developed T-cell acute lympho- blastic leukemia (ALL) with the sole abnormality of 47,XY,+Y.

CASE REPORT

A 66-year-old man was admitted to our hospital for mal- aise in March 1994. The patient's hemoglobin was 4.4 g/ dL, platelet count was 43 × 109/L and white blood cell count was 69 x 109/L with 99% small lymphoblasts with homogeneous nuclear chromatin. The bone marrow was

From the Department of Internal Medicine, Takamatsu Red Cross Hospital (A. W., Y. K., T. N., T. U.), Kagawa; Faculty of Phar- maceutical Sciences, Tokushima Bunri University (K. S.), Toku- shima; and Division of Genetic Research, SRL Inc. (K. H.), Tokyo, Japan.

Address reprint requests to Ayako Watanabe, Department of Internal Medicine, Takam~tsu Red Cross Hospital, 4-1-3 Ban-cho, Takamatsu-city, Kagawa 760, Japan.

Received August 10, 1995; accepted December 10, 1995.

Cancer Genet Cytogenet 89:85--87 (1996) © Elsevier Science Inc., 1996 655 Avenue of the Americas , New York, NY 10010

hyperplastic and infiltrated by lymphoblasts as seen in the peripheral blood. These cells were stained negative for myeloperoxidase but positive for acid phosphatase. Elec- tron microscopy showed scanty cytoplasm, poor progres- sion of cell organelle and homogeneous nuclear chromatin. Surface markers of these cells were assessed using mono- clonal antibodies and were as follows: CD1, 0%; CD2, 93%; CD3, 0%; CD4, 0%; CD5, 0%; CD7, 74%; CD8, 1%; CD10, 0%; CD13, 6%; CD14, 0%; CD19, 0%, CD20; 0%; CD33, 0%; CD34, 0%; HLA-DR, 21%. Both terminal deoxy- nucleotidyl transferase (TdT) and cytoplasmic CD3 were positive. Southern blot analysis revealed that T-cell recep- tor (TCR) [3, % and ~ genes were germline, and also JH and JK remained in germline configurations. Sex-determining Y (SRY) and a major component of the human Y chromo- some specific repeated DNA family (DYZ1) were carried out by polymerase chain reaction and Southern blot analy- sis to assess the possible differences between the bone marrow cells in the leukemic stage and those in the remis- sion stage. The same bands were detected in these two cells both on SRY and DYZ1, and other abnormal bands were not seen.

There was the complication of disseminated intravascu- lar coagulation. The patient was treated with doxorubicin, vincristine, prednisolone, heparin sodium, and antithrom- bin III concentrate, and remission was achieved. After two courses of consolidation chemotherapy, the patient was discharged from our hospital in November 1994, and has since received chemotherapy as an outpatient.

CYTOGENETIC STUDIES

Cytogenetic analysis was performed using the conven- tional trypsin Giemsa banding (G-banding) and quinacrine

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i m

20 21 22 X Y Y

Figure I G-banded bone marrow karyotype at the time of diagnosis from the patient.

mustard banding (Q-banding) techniques. Unstimulated 24-hour cultures of the bone marrow cells at the time of diagnosis and remission, and 72-hour phytohemagglutinin (PHA)-stimulated culture of the peripheral blood at the time of remission were analyzed. Twenty metaphase spreads were fully analyzed in accordance with ISSN (1991). The bone marrow aspirate at the time of diagnosis was 47, XY,+Y in all metaphase cells observed by G- and Q-band- ing techniques (Figure 1). No other structural aberration was seen. At remission, the bone marrow cells and the PHA-stimulated peripheral blood lymphocytes showed a normal karyotype of 46,XY.

DISCUSSION

Initially we considered the patient to be a constitutional 47,XYY male who had developed T-cell ALL, but the bone marrow cells and the PHA-stimulated peripheral blood lymphocytes in the remission stage showed a normal kary- otype of 46,XY. To our knowledge, this is the first to be reported of T-cell ALL with a sole abnormal karyotype of 47,XY,+Y. Previously, 25 cases of constitutional 47,XYY males who developed leukemias have been described and

these included AML in eleven patients, ALL in seven, chronic myelogeneous leukemia in three, acute leukemia in two, and myelodysplastic syndromes (MDS) in two patients. The incidence was estimated five- to six-fold higher than in the normal population [9], and it has been suggested that constitutional XYY, like trisomy 21, con- tributes to an increased risk of leukemia [10]. However, a recent study has reported that these associations are an accidental coincidence, according to the investigation of XY/XYY mosaics, because the leukemic clone originated from normal XY-bearing stem cells [11]. As for the non- constitutional case, three AMLs, which included one M5 AML [4] and one M4 AML [5], and RAEB-T [8] with an extra Y chromosome as the sole clonal abnormality have been reported. An extra Y chromosome as the non-sole clonal change also has been reported in three hairy cell leukemias [7, 12] and one refractory anemia [13]. Xiao and colleagues [7] have observed an extra Y chromosome in the established B-cell chronic leukemic cell lines as the sole karyotypic change and have concluded that an extra Y chromosome may be a new primary anomaly in chronic lymphoproliferative disorders.

No oncogene on the Y chromosome has been detected,

Extra Y in ALL 8 7

however, a recent repcrt has demonstrated that SRY pro- tein enhances transcript ion of the fos-related antigen 1 gene that is closely related to the protooncogene c-fos [14]. In addition, the localization of the human granulocyte- macrophage colony st imulat ing factor receptor gene to the X-Y pseudoautosomal region has been reported and has been suggested to be important in unders tanding the gen- eration of M2 AML [15], and AMLs or MDSs with an extra Y chromosome might have some association with this gene. But the relationship between T-cell ALL and the extra Y chromosome is not yet clearly understood.

Our patient was diagnosed with immature T-cell leuke- mia because the leukemic cells expressed only CD2, CD7, TdT, and cytoplasmic CD3, and the TCR did not rearrange. T-cell ALL is known to be highly heterogeneous and pos- sesses a mult i l ineage potential [16, 17]. There may be vari- ous causes in the development of T-cell leukemia. In the present case, only leukemic cells had the extra Y chromo- some and were immature. This observation speculates that an extra Y chromosome may be a kind of new chromo- somal abnormali ty of %cell ALL.

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