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Long arm deletion of chromosome no. 5 in a case of Philadelphia chromosome-positive chronic myelocytic leukemia
Long Arm Deletion of Chromosome No. 5 in a Case of Philadelphia Chromosome-positive Chronic Myelocytic Leukemia Takafumi Tomiyasu, Motomichi Sasaki, and Syuiti Abe
ABSTRACT: A 28-year-old woman with chronic myelocytic leukemia was shown to have a long arm deletion of chromosome No. 5 (5q--) in addition to a Philadelphia chromosome (Ph ~) in the leukemic cells. Banding analysis revealed an interstitial deletion, del(5) (q14q23) and a standard Ph I translocation, t(9;22) (q34;q11). Based at the present and 37 previously reported cases of the 5 q - anomaly in various hematologic disorders, a deleted segment between bands 5q22 and 5q23 is proposed to be common to all of the cases so far studied.
INTRODUCTION A long arm deletion of chromosome No. 5 (5q--) was first described by Van Den Berghe et al. [1] as a consistent karyotypic anomaly in the bone marrow cells of three patients with refractory anemia. Subsequently, the 5 q - anomaly was reported to occur in some other cases of refractory anemia [2,3], myelofibrosis [4,5], thrombocythemia [6], acute myelogenous leukemia (AML), both with and without preceding preleukemic disorders [ 7 - 9 , 2 2 - 2 4 ] , multiple myeloma [10], and acute lymphoblastic leukemia [11,23]. In this article, we describe a case of chronic myelocytic leukemia (CML) in which the 5 q - anomaly was present in addition to the standard Philadelphia chromosome (Ph') translocation. CASE REPORT
A 28-year-old w o m a n admitted to the Hokkaido University Hospital on September 5, 1977, was noted to have slight gingival hemorrhage and severe splenomegaly. Hematological examination done on September 9, 1977, revealed a markedly elevated leukocyte count of 285.0 × 103/ram3 with 3% myeloblasts and 24% promyelocytes in the peripheral blood (Table 1). Leukocyte alkaline phosphatase (LAP) score was 55 (normal 169.5-367.0), LAP rate 34 (normal 60.5-99.5), and peroxidase 93% positive. A diagnosis of CML was made, and the patient was treated with daily administration of busulfan, started on September 23, 1977. Incomplete remission was obtained, and she was discharged from the hospital 3 months after initiation of the chemotherapy. Maintenance therapy with busulfan, twice a month, was c o n t i n u e d until January
From the ChromosomeResearchUnit, Facultyof Science,HokkaidoUniversity,Sapporo, Japan. Address requests for reprints to: Professor Motomichi Sasaki, Chromosome Research Unit, Faculty of Science, Hokkaido University, North 10, West 8, Sapporo 060, Japan. Received February 8, 1980; accepted May 13, 1980.
309 Copyright © ElsevierNorth Holland,Inc., 1980 52 VanderbiltAve.,New York,NY 1 0 0 1 7
CancerGeneticsand Cytogenetics2,309- 315 (1980) 0165-4608/80/06030907502.25
1
CP CP IR BP BP IR IR BP BP
Phase or response ~
87.0 11.3 6.8 65.0 89.0
4.0
Mb (%)
Hematological
0 3.3 2.4 0 0
14.4
Pm (%)
12.0 48.0 36.0 30.0 0
995.0
43.5 5.6 4.9 27.3 0.9
126.0 0 24.0 89.0 6.0 1.0 71.0 59.0
3.0
Mb (%)
blood
2.0 3.0 0 2.0 2.0 1.0 0
24.0
Pm (%)
30.2 114.0 219.0 2.1 8.4 173.0 0.6
285.0
302.0 374.0 319.0 285.0 320.0 356.0 289.0
404.0
11.8 10.2 9.2 8.6 9.7 11.1 8.0
11.6
P e r i p h e r a l b l o o d ~" WBC RBC Hb (Xl0:~/mm :~) ( X l 0 4 / m m :~) (g/dl)
~'WBC-- white blood cells; RBC
red blood cells; Hb = hemoglobin; Plat = platelets.
~Mb = myeloblasts; P m - promyelocytes; Mega = megakaryocytes; Nucl = nucleated ceils; M/E ratio = myeloid/erythroid cells ratio.
59.0:1 1.6:1 5.2:1 60.0:1 73.0:1
48.5:1
M/E ratio
and peripheral
Bone marrow b Mega Nucl (per m m :~) ( X l 0 4 / m m :~)
data on bone marrow
"CP = chronic phase; IR= incomplete remission; BP = blastic phase.
5/2/79 5/25/79
4/9/79
2/7/79 3/19/79
1/16/79
12/19/78
9/14/77
9/9/77
Date
Table
31.2 45.3 11.0 16.0 30.0 15.0 5.0
31.0
(XlO41mm~)
Plat
311
5 q - in Chronic Myelocytic Leukemia
1979. The peripheral blood taken on January 16, 1979, showed a progression of CML with 24% myeloblasts. The patient was transferred to the Sapporo National Hospital on February 5, 1979. Hematological e x a m in a t i o n done on February 7, 1979, revealed a blastic transformation with 87 and 89% myeloblasts in bone marrow and peripheral blood, respectively. Following intensive c h e m o t h e r a p y with 6-mercaptopurine, prednisolone, vincristine, and c y c l o p h o s p h a m i d e , i n c o m p l e t e remission was induced, and m a i n t a i n e d for 3 months. Hematological ex am i n at i o n m a d e on May 2, 1979, disclosed the inevitable relapse, w i t h a high frequency of myeloblasts in the m a r r o w (65%) and blood (71%). T h e patient died on June 3, 1979.
CYTOGENETIC FINDINGS A serial c h r o m o s o m e study was performed over the clinical course of the patient on direct preparations of cells from bone marrow aspirates. Peripheral blood cultures with or w i t h o u t p h y t o h e m a g g l u t i n i n (PHA) were also used on some occasions. Karyotype analysis was clone by means of the Q- and R-banding t e c h n i q u e [12] with some slight modification. Table 2 s u m m a r i z e s the results of the c h r o m o s o m e analysis. Th e first chromosome e x a m i n a t i o n revealed the existence of two cell lines, 46,XX,Ph' and 46,XX,Ph~,Sq - in both direct bone marrow sample and cultured peripheral blood w i t h o u t PHA. T h e latter karyotype was found in about one-third of the marrow cells and one-quarter of the b lo o d cells examined. Th e banding analyses unequivocally showed that the Pht was d e r i v e d from the standard type translocation, t(9;22) (q34;q11), and that the 5 q - was d u e to an interstitial deletion of bands 5q14 to 5q23 (Fig. 1). T h e r e was no sign of translocation of the deleted material from the 5(tto any other m e m b e r of the c o m p l e m e n t . PHA-stimulated peripheral l y m p h o c y t e s cultured on December 19, 1978, exhibited only d i p l o i d cells w i t h a normal female karyotype, w h e r e a s u n s t i m n l a t e d blood cells cultured on the same day s h o w e d excl u s i v el y a 46,XX,PhLSq- karyotype. Thereafter, the 46,XX,Ph ~ cells, w h i c h had p r e d o m i n a t e d at first, disappeared and the leukemic cell populations of bone marr o w and peripheral b l o o d were c o m p l e t e l y replaced by cells containing both the P h i and 5q-. It was n o t e d that an u n u s u a l l y high percentage (24%) of p o l y p l o i d cells w i t h Ph ~ and 5 q - was observed in a m a r r o w sample e x a m i n e d on February 7, 1979. Also notable was the d e v e l o p m e n t of some additional karyotypic anoma-
Table 2
Cytogenetic data
Date
Materiala
9/14/77
BM(D) PB(C) PB(C) PB[PHA) BM(I)} BM(D) BM(D) PB(C) BM(D) BM(D)
12/19/78 2/7/79 3/19/79 4/9/79 5/2/79 5/25/79
No. of cells with No. of chromosome no. of cells =<44 45 46 _-->47 analyzed 1
2
3
1
1 1 1 2
1 2 4 2 3
No. of cells with normal karyotype
tlgq+;22q--I
t(9q+;22q-),5q-11
27
30
0
19
16
19
34 24 17 46 35 8 15 23
35 24 18 49 42 13 20 30
0 0
14 0
2 4 3 2
24 0 0 0 0 0 O
0 0 0 0 0 0 0
5
35 O 18 49 42 130 20b 30t'
"BM- bone marrow; PB = peripheral blood;D= direct preparation; C= culture without PHA;PHA= culture with PHA. ~'Various structural and numerical changes were observed in addition to the Ph ~and 5q~. See text for details.
Q-banded karyotype of a cell with 46,XX,t(9;22) (q34;q11), del (5) (q14q23) from a peripheral blood culture without PHA done on September 14, 1977. Arrows indicate the 5 q - and standard Ph ~translocation between chromosomes No. 9 and 22. R-banded partial karyotype for chromosomes No. 4 and 5 is shown in the inset and the break points, 5q14 and 5q23, are noted.
Figure 1
313
5 q - in Chronic Myelocytic Leukemia
lies besides the Ph 1 and 5q-, which appeared during the terminal phase of the disease. Although such abnormalities were highly variable from cell to cell, a loss of chromosome No. 2 or chromosome No. 7 occurred rather frequently.
DISCUSSION The 5 q - a n o m a l y has been reported to occur in various hematologic diseases, including mostly myeloproliferative disorders rather than l y m p h o i d ones. They are essentially anemia or AML with or without a long standing preleukemic phase [7-9]. The occurrence of the 5 q - in CML has not been reported to date, except for one possible case, w h i c h was studied without b a n d i n g analysis [13]. The present case is therefore the first instance of CML with a verified 5 q - anomaly. The 5q-- a n o m a l y is frequently accompanied by other chromosomal abnormalities [ 7 - 9 , 2 2 - 2 4 ] . Although the etiological significance of the 5 q - a n o m a l y in various types of hematologic disorders has remained obscure, Van Den Berghe et al. [5] postulated that the appearance of the 5 q - anomaly may herald the onset of acute leukemia and that the 5 q - a n o m a l y is almost invariably associated with overt malignancy irrespective of the nature of the concurrent karyotypic anomalies. In the present case, the 5 q - anomaly occurred together with a Ph ], and these anomalies persisted throughout the entire clinical course of the disease. The fact that PHA-stimulated blood cells of the patient showed a normal karyotype indicates that both the Ph' and 5 q - are not constitutional in origin. The data also suggested that the 5 q - in this case has occurred in a preexisting phi-positive leukemic cell, since the 46,XX,Ph ] cells that predominated at diagnosis were completely replaced by the 46,XX,Phl,5q- cells in later samples. This may be a reflection of a clonal evolution of the latter cell type due to its selective growth advantage over the former one. Whether the i n c l u s i o n of the 5 q - in the Phi-positive cells was causally related to the acute transformation is u n k n o w n . The fact that the 5 q - a n o m a l y in the present case occurred prior to the onset of blastic phase may or may not have been fortuitous. Figure 2 Regions involved in the 5q- anomaly in 38 patients with various hematologic diseases. Each vertical line represents the deleted region of the 5q-. The number in parentheses indicates the number of cases reported. The area between dashed horizontal lines is common to all of the 38 cases. RA-refractory anemia [1- 3,15-19]; AML-acute myelogenous leukemia [7 - 10,20 - 24]; MF - myelofibrosis [4,5] ; TC - thrombocythemia [6]; MM - multiple myeloma [10]; ALL-acute lymphoblastic leukemia [11,23]; CML-chronic myelocytic leukemia [present case].
(11) (2) ( I ) RA
(I)
(I)
(5) (2) (2) ( I )
(I)
AML
(I)
(I)
(I)
(3) ( I ) MF
{I)
(I)
ALL
(I)
(1) ( I )
TC
M M CML
314
T. T o m i y a s u , M. Sasaki, a n d S. A b e
T h e 5q-- a n o m a l y n o t e d i n s o m e 38 c a s e s of v a r i o u s h e m a t o l o g i c d i s o r d e r s app e a r s to i n c l u d e a n i n t e r s t i t i a l or t e r m i n a l d e l e t i o n , as i l l u s t r a t e d i n F i g u r e 2. E v e n t h o u g h t h e d e l e t e d s e g m e n t is v a r i a b l e , a s p e c i f i c r e g i o n b e t w e e n b a n d s 5q22 a n d 5q23 is m i s s i n g i n all of t h e cases, i n c l u d i n g t h e p r e s e n t one. A s i m i l a r a t t e m p t at reg i o n a l a s s i g n m e n t h a s b e e n m a d e b y R o w l e y [14] for c l o n a l a b e r r a t i o n s l e a d i n g to a n e x c e s s or p a r t i a l e x c e s s of c h r o m o s o m e No. 1 i n a v a r i e t y of h e m a t o l o g i c d i s o r ders, s u c h as a c u t e l e u k e m i a , p o l y c y t h e m i a vera, a n d m y e l o f i b r o s i s . T h e p r e s e n c e of a c o m m o n d e l e t e d r e g i o n i n t h e 5 q - a n o m a l y w o u l d i m p l y t h e p o s s i b l e r e l e v a n c e of c e r t a i n g e n e loci o n t h a t r e g i o n to h e m a t o l o g i c d i s e a s e s . T h i s p o s s i b i l i t y h a s b e e n s u g g e s t e d a n d f u l l y d i s c u s s e d b y R o w l e y [14] for t h e a f o r e m e n t i o n e d i n s t a n c e of t r i s o m y 1 a n d s e v e r a l o t h e r n o n r a n d o m c h a n g e s of c h r o m o s o m e s i n v a r i o u s b l o o d disorders. The authors wish to thank Dr. K. Kamishima of the Hokkaido University Hospital and Dr. C. Mikuni of the Sapporo National Hospital for the clinical and hematological data on the patient. This study was supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan.
REFERENCES 1. Van Den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G (1974): Distinct haematological disorders with deletion of long arm of No. 5 chromosome. Nature 251, 437-438. 2. Sokal G, Michaux JL, Van Den Berghe H, Cordier A, Rodhain J, Ferrant A, Moriau M, De Bruyere M, Sonnet J (1975): A new hematologic syndrome with a distinct karyotype: the 5 q - chromosome. Blood 4 6 , 5 1 9 - 533. 3. Verhest A, Van Schoubroeck F, Wittek M, Naets ~P, Denolin-Reubens R (1976): Specifity of the 5 q - chromosome in a distinct type of refractory anemia. J Natl Cancer Inst 56, 1053 - 1054. 4. Whang-Peng J, Lee E, Knutsen T, Chang P, Nienhuis A (1978): Cytogenetic studies in patients with myelofihrosis and myeloid metaplasia. Leukemia Res 2, 41 - 56. 5. Van Den Berghe H, Broeckaert-Van Orshoven A, Louwagie A, Verwilghen R, Michaux IL, Sokal G (1979): Transformation of polycythemia vera to myelofibrosis and late appearance of a 5 q - chromosome anomaly. Cancer Genet Cytogenet 1,157 - 167. 6. Nowell P, Finan J (1978): Chromosome study in preleukemic states. IV. Myeloproliferative versus cytopenic disorders. Cancer 42, 2 2 5 4 - 2261. 7. Rowley ID (1976): 5q-- acute myelogenous leukemia: reply. Blood 48,626. 8. Van Den Berghe H, David G, Michaux JL, Sokal G, Verwilghen R (1976): 5q-- acute myelogenous leukemia. Blood 48, 624-625. 9. Petit P, Van Den Berghe H (1979): The 5q-- and additional chromosome anomalies in two patients with acute myeloid leukemia. Ann Cenet 22,103 - 105. 10. Liang W, Hopper JE, Rowley JD (1979): Karyotypic abnormalities and clinical aspects of patients with multiple myeloma and related paraproteinemic disorders. Cancer 44, 630-644. 11. Abe S, Kohno S, Kubonishi I, Minowada J, Sandberg AA (1979): Chromosomes and causation of h u m a n cancer and leukemia. XXXIII. 5 q - in a case of acute lymphoblastic leukemia (ALL). Am J Hematol 6, 2 5 9 - 266. 12. Niikawa N, Kajii T (1975): Sequential Q - and acridine orange-marker technique. Humangenetik 30, 83 -90. 13. Miyamoto N (1974): A long-term cytogenetic survey on fifty patients with chronic myelogenous leukemia (in Japanese). Fukuoka Acta Med 65,601 - 621. 14. Rowley JD (19771: Mapping of h u m a n chromosomal regions related to neoplasia: evidence from chromosomes 1 and 17. Proc Natl Acad Sci USA 74, 5 7 2 9 - 5733. 15. Prieto F, Balida L, Calabuig JR, Mayans J, Perez-Sirvent ML, Martinez J, Luno E, Marty ML
5q-- in C h r o n i c M y e l o c y t i c L e u k e m i a
315
(1976): Alteraciones cromosomicas en las anemias refractarias con mieloblastosis parcial. Sangre 21(3-B), 701 - 712. 16. Kaffe S, Hsu LYF, Hoffman R, Hirschhorn K (1978): Association of 5q-- and refractory anemia. Am J Hematol 4,269 - 272. 17. Mahmood T, Robinson WA, Hamstra RD, Wallner SF (1979): Macrocytic anemia, thrombocytosis and nonlobulated megakaryocytes: the 5 q - syndrome, a distinct entity. Am J Med 6 6 , 9 4 6 - 950. 18. Jume'an HG, Libnoch JA (1979): 5 q - myelodysplasia terminating in acute leukemia. Ann Intern Med 9 1 , 7 4 8 - 749. 19. Van Den Berghe H, Petit P, Broeckaert-Van Orshoven A, Louwagie A, De Baere H, Verwilghen R (1979): Simultaneous occurrence of 5 q - and 21q-- in refractory anemia with thrombocytosis. Cancer Genet Cytogenet 1, 6 3 - 68. 20. Rowley JD (1975): Abnormalities of chromosome 1 in myeloproliferative disorders. Cancer 36, 1748 - 1757. 21. Cabrol C, Abele R (1978): Chromosome 5 q - dans les cellules medullaires d'un sujet atteint d'anemie ayant evolue en leucemie aigue indifferenciee. J Genet Hum 26, 195 - 202. 22. Oshimura M, Sonta S, Sandberg AA (1976): Trisomy of the long arm of chromosome #1 in human leukemia. J Natl Cancer Inst 56, 183 - 184. 23. Prigogina EL, Fleischman EW, Puchkova GP, Kulagina OE, Majakova SA, Balakirev SA, Frenkel MA, Khvatova NV, Peterson IS (1979): Chromosomes in acute leukemia. Hum Genet 53, 5 - 1 6 . 24. Testa JR, Mintz U, Rowley JD, Vardiman JW, Golomb HM (1979): Evolution of karyotypes in acute nonlymphocytic leukemia. Cancer Res 39, 3619 - 3627.
ABSTRACT: A 28-year-old woman with chronic myelocytic leukemia was shown to have a long arm deletion of chromosome No. 5 (5q--) in addition to a Philadelphia chromosome (Ph ~) in the leukemic cells. Banding analysis revealed an interstitial deletion, del(5) (q14q23) and a standard Ph I translocation, t(9;22) (q34;q11). Based at the present and 37 previously reported cases of the 5 q - anomaly in various hematologic disorders, a deleted segment between bands 5q22 and 5q23 is proposed to be common to all of the cases so far studied.
INTRODUCTION A long arm deletion of chromosome No. 5 (5q--) was first described by Van Den Berghe et al. [1] as a consistent karyotypic anomaly in the bone marrow cells of three patients with refractory anemia. Subsequently, the 5 q - anomaly was reported to occur in some other cases of refractory anemia [2,3], myelofibrosis [4,5], thrombocythemia [6], acute myelogenous leukemia (AML), both with and without preceding preleukemic disorders [ 7 - 9 , 2 2 - 2 4 ] , multiple myeloma [10], and acute lymphoblastic leukemia [11,23]. In this article, we describe a case of chronic myelocytic leukemia (CML) in which the 5 q - anomaly was present in addition to the standard Philadelphia chromosome (Ph') translocation. CASE REPORT
A 28-year-old w o m a n admitted to the Hokkaido University Hospital on September 5, 1977, was noted to have slight gingival hemorrhage and severe splenomegaly. Hematological examination done on September 9, 1977, revealed a markedly elevated leukocyte count of 285.0 × 103/ram3 with 3% myeloblasts and 24% promyelocytes in the peripheral blood (Table 1). Leukocyte alkaline phosphatase (LAP) score was 55 (normal 169.5-367.0), LAP rate 34 (normal 60.5-99.5), and peroxidase 93% positive. A diagnosis of CML was made, and the patient was treated with daily administration of busulfan, started on September 23, 1977. Incomplete remission was obtained, and she was discharged from the hospital 3 months after initiation of the chemotherapy. Maintenance therapy with busulfan, twice a month, was c o n t i n u e d until January
From the ChromosomeResearchUnit, Facultyof Science,HokkaidoUniversity,Sapporo, Japan. Address requests for reprints to: Professor Motomichi Sasaki, Chromosome Research Unit, Faculty of Science, Hokkaido University, North 10, West 8, Sapporo 060, Japan. Received February 8, 1980; accepted May 13, 1980.
309 Copyright © ElsevierNorth Holland,Inc., 1980 52 VanderbiltAve.,New York,NY 1 0 0 1 7
CancerGeneticsand Cytogenetics2,309- 315 (1980) 0165-4608/80/06030907502.25
1
CP CP IR BP BP IR IR BP BP
Phase or response ~
87.0 11.3 6.8 65.0 89.0
4.0
Mb (%)
Hematological
0 3.3 2.4 0 0
14.4
Pm (%)
12.0 48.0 36.0 30.0 0
995.0
43.5 5.6 4.9 27.3 0.9
126.0 0 24.0 89.0 6.0 1.0 71.0 59.0
3.0
Mb (%)
blood
2.0 3.0 0 2.0 2.0 1.0 0
24.0
Pm (%)
30.2 114.0 219.0 2.1 8.4 173.0 0.6
285.0
302.0 374.0 319.0 285.0 320.0 356.0 289.0
404.0
11.8 10.2 9.2 8.6 9.7 11.1 8.0
11.6
P e r i p h e r a l b l o o d ~" WBC RBC Hb (Xl0:~/mm :~) ( X l 0 4 / m m :~) (g/dl)
~'WBC-- white blood cells; RBC
red blood cells; Hb = hemoglobin; Plat = platelets.
~Mb = myeloblasts; P m - promyelocytes; Mega = megakaryocytes; Nucl = nucleated ceils; M/E ratio = myeloid/erythroid cells ratio.
59.0:1 1.6:1 5.2:1 60.0:1 73.0:1
48.5:1
M/E ratio
and peripheral
Bone marrow b Mega Nucl (per m m :~) ( X l 0 4 / m m :~)
data on bone marrow
"CP = chronic phase; IR= incomplete remission; BP = blastic phase.
5/2/79 5/25/79
4/9/79
2/7/79 3/19/79
1/16/79
12/19/78
9/14/77
9/9/77
Date
Table
31.2 45.3 11.0 16.0 30.0 15.0 5.0
31.0
(XlO41mm~)
Plat
311
5 q - in Chronic Myelocytic Leukemia
1979. The peripheral blood taken on January 16, 1979, showed a progression of CML with 24% myeloblasts. The patient was transferred to the Sapporo National Hospital on February 5, 1979. Hematological e x a m in a t i o n done on February 7, 1979, revealed a blastic transformation with 87 and 89% myeloblasts in bone marrow and peripheral blood, respectively. Following intensive c h e m o t h e r a p y with 6-mercaptopurine, prednisolone, vincristine, and c y c l o p h o s p h a m i d e , i n c o m p l e t e remission was induced, and m a i n t a i n e d for 3 months. Hematological ex am i n at i o n m a d e on May 2, 1979, disclosed the inevitable relapse, w i t h a high frequency of myeloblasts in the m a r r o w (65%) and blood (71%). T h e patient died on June 3, 1979.
CYTOGENETIC FINDINGS A serial c h r o m o s o m e study was performed over the clinical course of the patient on direct preparations of cells from bone marrow aspirates. Peripheral blood cultures with or w i t h o u t p h y t o h e m a g g l u t i n i n (PHA) were also used on some occasions. Karyotype analysis was clone by means of the Q- and R-banding t e c h n i q u e [12] with some slight modification. Table 2 s u m m a r i z e s the results of the c h r o m o s o m e analysis. Th e first chromosome e x a m i n a t i o n revealed the existence of two cell lines, 46,XX,Ph' and 46,XX,Ph~,Sq - in both direct bone marrow sample and cultured peripheral blood w i t h o u t PHA. T h e latter karyotype was found in about one-third of the marrow cells and one-quarter of the b lo o d cells examined. Th e banding analyses unequivocally showed that the Pht was d e r i v e d from the standard type translocation, t(9;22) (q34;q11), and that the 5 q - was d u e to an interstitial deletion of bands 5q14 to 5q23 (Fig. 1). T h e r e was no sign of translocation of the deleted material from the 5(tto any other m e m b e r of the c o m p l e m e n t . PHA-stimulated peripheral l y m p h o c y t e s cultured on December 19, 1978, exhibited only d i p l o i d cells w i t h a normal female karyotype, w h e r e a s u n s t i m n l a t e d blood cells cultured on the same day s h o w e d excl u s i v el y a 46,XX,PhLSq- karyotype. Thereafter, the 46,XX,Ph ~ cells, w h i c h had p r e d o m i n a t e d at first, disappeared and the leukemic cell populations of bone marr o w and peripheral b l o o d were c o m p l e t e l y replaced by cells containing both the P h i and 5q-. It was n o t e d that an u n u s u a l l y high percentage (24%) of p o l y p l o i d cells w i t h Ph ~ and 5 q - was observed in a m a r r o w sample e x a m i n e d on February 7, 1979. Also notable was the d e v e l o p m e n t of some additional karyotypic anoma-
Table 2
Cytogenetic data
Date
Materiala
9/14/77
BM(D) PB(C) PB(C) PB[PHA) BM(I)} BM(D) BM(D) PB(C) BM(D) BM(D)
12/19/78 2/7/79 3/19/79 4/9/79 5/2/79 5/25/79
No. of cells with No. of chromosome no. of cells =<44 45 46 _-->47 analyzed 1
2
3
1
1 1 1 2
1 2 4 2 3
No. of cells with normal karyotype
tlgq+;22q--I
t(9q+;22q-),5q-11
27
30
0
19
16
19
34 24 17 46 35 8 15 23
35 24 18 49 42 13 20 30
0 0
14 0
2 4 3 2
24 0 0 0 0 0 O
0 0 0 0 0 0 0
5
35 O 18 49 42 130 20b 30t'
"BM- bone marrow; PB = peripheral blood;D= direct preparation; C= culture without PHA;PHA= culture with PHA. ~'Various structural and numerical changes were observed in addition to the Ph ~and 5q~. See text for details.
Q-banded karyotype of a cell with 46,XX,t(9;22) (q34;q11), del (5) (q14q23) from a peripheral blood culture without PHA done on September 14, 1977. Arrows indicate the 5 q - and standard Ph ~translocation between chromosomes No. 9 and 22. R-banded partial karyotype for chromosomes No. 4 and 5 is shown in the inset and the break points, 5q14 and 5q23, are noted.
Figure 1
313
5 q - in Chronic Myelocytic Leukemia
lies besides the Ph 1 and 5q-, which appeared during the terminal phase of the disease. Although such abnormalities were highly variable from cell to cell, a loss of chromosome No. 2 or chromosome No. 7 occurred rather frequently.
DISCUSSION The 5 q - a n o m a l y has been reported to occur in various hematologic diseases, including mostly myeloproliferative disorders rather than l y m p h o i d ones. They are essentially anemia or AML with or without a long standing preleukemic phase [7-9]. The occurrence of the 5 q - in CML has not been reported to date, except for one possible case, w h i c h was studied without b a n d i n g analysis [13]. The present case is therefore the first instance of CML with a verified 5 q - anomaly. The 5q-- a n o m a l y is frequently accompanied by other chromosomal abnormalities [ 7 - 9 , 2 2 - 2 4 ] . Although the etiological significance of the 5 q - a n o m a l y in various types of hematologic disorders has remained obscure, Van Den Berghe et al. [5] postulated that the appearance of the 5 q - anomaly may herald the onset of acute leukemia and that the 5 q - a n o m a l y is almost invariably associated with overt malignancy irrespective of the nature of the concurrent karyotypic anomalies. In the present case, the 5 q - anomaly occurred together with a Ph ], and these anomalies persisted throughout the entire clinical course of the disease. The fact that PHA-stimulated blood cells of the patient showed a normal karyotype indicates that both the Ph' and 5 q - are not constitutional in origin. The data also suggested that the 5 q - in this case has occurred in a preexisting phi-positive leukemic cell, since the 46,XX,Ph ] cells that predominated at diagnosis were completely replaced by the 46,XX,Phl,5q- cells in later samples. This may be a reflection of a clonal evolution of the latter cell type due to its selective growth advantage over the former one. Whether the i n c l u s i o n of the 5 q - in the Phi-positive cells was causally related to the acute transformation is u n k n o w n . The fact that the 5 q - a n o m a l y in the present case occurred prior to the onset of blastic phase may or may not have been fortuitous. Figure 2 Regions involved in the 5q- anomaly in 38 patients with various hematologic diseases. Each vertical line represents the deleted region of the 5q-. The number in parentheses indicates the number of cases reported. The area between dashed horizontal lines is common to all of the 38 cases. RA-refractory anemia [1- 3,15-19]; AML-acute myelogenous leukemia [7 - 10,20 - 24]; MF - myelofibrosis [4,5] ; TC - thrombocythemia [6]; MM - multiple myeloma [10]; ALL-acute lymphoblastic leukemia [11,23]; CML-chronic myelocytic leukemia [present case].
(11) (2) ( I ) RA
(I)
(I)
(5) (2) (2) ( I )
(I)
AML
(I)
(I)
(I)
(3) ( I ) MF
{I)
(I)
ALL
(I)
(1) ( I )
TC
M M CML
314
T. T o m i y a s u , M. Sasaki, a n d S. A b e
T h e 5q-- a n o m a l y n o t e d i n s o m e 38 c a s e s of v a r i o u s h e m a t o l o g i c d i s o r d e r s app e a r s to i n c l u d e a n i n t e r s t i t i a l or t e r m i n a l d e l e t i o n , as i l l u s t r a t e d i n F i g u r e 2. E v e n t h o u g h t h e d e l e t e d s e g m e n t is v a r i a b l e , a s p e c i f i c r e g i o n b e t w e e n b a n d s 5q22 a n d 5q23 is m i s s i n g i n all of t h e cases, i n c l u d i n g t h e p r e s e n t one. A s i m i l a r a t t e m p t at reg i o n a l a s s i g n m e n t h a s b e e n m a d e b y R o w l e y [14] for c l o n a l a b e r r a t i o n s l e a d i n g to a n e x c e s s or p a r t i a l e x c e s s of c h r o m o s o m e No. 1 i n a v a r i e t y of h e m a t o l o g i c d i s o r ders, s u c h as a c u t e l e u k e m i a , p o l y c y t h e m i a vera, a n d m y e l o f i b r o s i s . T h e p r e s e n c e of a c o m m o n d e l e t e d r e g i o n i n t h e 5 q - a n o m a l y w o u l d i m p l y t h e p o s s i b l e r e l e v a n c e of c e r t a i n g e n e loci o n t h a t r e g i o n to h e m a t o l o g i c d i s e a s e s . T h i s p o s s i b i l i t y h a s b e e n s u g g e s t e d a n d f u l l y d i s c u s s e d b y R o w l e y [14] for t h e a f o r e m e n t i o n e d i n s t a n c e of t r i s o m y 1 a n d s e v e r a l o t h e r n o n r a n d o m c h a n g e s of c h r o m o s o m e s i n v a r i o u s b l o o d disorders. The authors wish to thank Dr. K. Kamishima of the Hokkaido University Hospital and Dr. C. Mikuni of the Sapporo National Hospital for the clinical and hematological data on the patient. This study was supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture, Japan.
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