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Chronic myelomonocytic leukemia with trisomy 8 and a related clone with trisomy 8 and t(15;17)
Chronic Myelomonocytic Leukemia with Trisomy 8 and a Related Clone with Trisomy 8 and t(15;17) Willard T. Dalton, Jr., Ann Cork, Sanford A. Stass, and Jose M. Trujillo
ABSTRACT: We describe o patient with chronic myclomonocytic h;ukemia who showed trisomy 8 in 100% of his bone marrow metaphases. Of interest was the finding that 20% of the Giemsabanded metaphases also showed t(15;17)(q22;q21), with breukpoints indistinguishable from those seen in cases of acute progranulocytic leukemia (APL). The patient showed no morpholagic or clinical evidence of APL, and he died after 6 months, with no evidence that the disease had progressed to acute leukemia. Although cytogeneticully the breakpoints appeared to he the same as those in APt,, we suspect that this patient's translncation may have differed at the molecular level from the t(15;17) commonly seen in API..
INTRODUCTION
There is a very strong association between t(15;17)(q22;q21) and acute progranulocytic leukemia (APL) (FAB classification M3 [1]) in both its hypergranular [2] and its variant, or microgranular form [3, 4]. Most patients with API,-M3 can be shown to have t(15;17) in their bone marrow metaphases. I,arson et al. [5] have demonstrated this translocation in all of their M3 patients, although other investigators find t(15;17) infrequently [6, 7]. This variability is the result, at least in part, of differences in the way the individual laboratories process bone marrow samples, with longer periods of culture favoring the recovery of metaphases with t(15;17) [7]. The experience with regard to the converse relationship, in contrast, is quite uniform: when t(15;17) is found as an acquired abnormality in hematologic malignancies, the bone marrow predictably shows abnormal progranulocytes with M3 morphology. This has held true even in u n u s u a l circumstances. Two patients with Phpositive chronic: granulocytic leukemia developed blast crisis, at which time they showed t(15;17) in more than half of their Ph-positive metaphases, and sllowed M3 morphology in their bone marrows [8, 9]. In another instance, a patient with acute myelomonocytic leukemia with abnormal eosinopbils (t"AB M4Eo [10]) and inv(16}(p13q22) had a minor related clone with both inv(16}(p13q22) and t(15;17)
From the Division of Laboratory Medicine, The Universityof Texas. M. D. Anderson llospital and Tumor Institute.ftouston, TX Address requests for reprints to Dr. Willard T. Dalton, Jr. Division of l.obaratory Medicine, Box 73, M. D. Anderson Hospital and Tumor Institute, 1515 Holcombe Blvd., Houston, TX 77030. Received March 16, 1987; accepted December 14. 1987.
287 'V)1988 W. T. Dalton.Jr.
Cancer (.;enet Cytogenet32:287-292 [1.q881
288
W . T . Dalton, Jr., et al. and a corresponding minor population of abnormal progranulocytes with M3 morphology in his bone marrow [11[. In large series reporting the cytogenetics of patients with preleukemic or m y e l o d y s p l a s t i c syndromes (MDS), one notable feature is the consistent failure to find t(15;17) [12, 13J. We now report a patient with trisomy 8 and a related clone with trisomy 8 and t(15;17) who had a slowly progressing MDS for more than 6 months, and who died without apparent transformation to acute leukemia.
CASE REPORT The patient was a 67-year-old man who was referred to M. D. Anderson Hospital in December 1977 with a diagnosis of preleukemia. During the previous summer he had noticed ecchymoses on his skin, and they had been increasing in number. He had diabetes mellitus, mild emphysema, and severe food and drug allergies. Physical examination failed to reveal l y m p h a d e n o p a t h y or hepatosplenomegaly. Initial peripheral blood counts showed a hemoglobin count of 11.8 g/dl, mean corpuscular volume 109 fl, platelet count 56 × 10*~/l,, and a leukocyte count of 8.1 × 10~J/L, with 25% mature neutrophils, 36% lymphocytes, 26% monocytes, 6% eosinophils, 1% basophils, 5% metamyelocytes, and 1% myelocytes. Prothrombin time, partial thromboplastin time, and levels of fibrinogen and fibrin degradation products were within normal limits. His leukocyte alkaline phosphatase (LAP) score was low at 1. His vitamin B,2 level was 888 pg/ml (n = 250 to 1000) and folate level 25.7 ng/ml (n = 4 to 16) (both done at the referring institution). Total serum protein was 7.8 g/dl, and albumin 4.5 g/dl. Serum i m m u n o g l o b u l i n assays showed: IgG 1669 mg/dl (n = 650 to 1750), IgA 285 mg/dl (n - 75 to 330), and lgM 43 mg/dl (n = 30 to 225). Thus, he had a borderline high IgG; a serum protein electrophoresis indicated polyclonal gamma globulins. A bone marrow aspirate showed a 70% cellularity with 6% blasts, 4% monocytes, and dysplasias of all three cell lines, consistent with a m y e l o d y s p l a s t i c process (Fig. 1). No Auer rods or abnormal progranulocytes of the type seen in FAB-M3 were identified. Based on the peripheral blood and bone marrow findings, this process was classified as chronic myelomonocytic leukemia (CMMoL) in accordance with FAB criteria [14]. Four additional bone marrow aspirates obtained during the next 6 months showed an increasing percentage of monocytes, but no other substantial changes (Table 1). The peripheral blood leukocyte counts rose steadily during this time, with an increasing absolute monocytosis. The patient died in July 1978 without clinical evidence of transformation to acute leukemia, although no bone marrow aspirates were obtained during the final 2 months of his life. CYTOGENETIC STUDIES Methods Chromosome studies were performed on the initial bone marrow aspirate and peripheral blood sample obtained in December 1977. Briefly, these studies included culturing the bone marrow cells overnight at 37°C and culturing the peripheral blood cells for 24 and 48 hours without stimulation and for 72 hours with phytohemagglutinin (PHA) stimulation. G-banded chromosomes were obtained by exposing the air-dried preparations made from the bone marrow culture to a 1.5 minute trypsin pretreatment followed by 1.5 minute Giemsa staining at pH 6.8. Twentyfive well-spread metaphases from the bone marrow preparations were analyzed, seven from the unstimulated peripheral blood preparations and 16 from the PHA-
C M M o L w i t h T r i s o m y 8 a n d t(15;17)
289
,/
t,
F i g u r e 1 Bone marrow smear. (A) Granulopoiesis is shifted to the le.ft and some hyposegmented neutrophils are present (arrows). Blasts are slightly i,lcreased (arrowhead). (B] Megakaryocytes tend to be small and hyposegmented. No cells resembling lhe abnormal progranulocytes ~f FAB-M3 are present. (Wright-(;iemsa stain)
0 0 -
35 40 -
59 57 110
35.5 42.3 50.0
4178 5176 6178
"Cellularity was visually estimated from histologic sections of aspirated bone marrow particles,
0 -
Blasts (%)
26 -
(%)
56 -
Monocytes
8.1 -
(X lOgiL)
12177 l/78
Platelets
blood
over time
Peripheral
data on CMMoL patient
WBC (x10%)
Hematologic
Date (mo/yr)
Table 1
70 80 75 70 -
Cellularity
(%)’
6 12 10 7 -
Blasts (%)
Bone marrow
4 4 11 13 -
Monocytes
(%)
0
s:
291
CMMoL with Trisomy 8 and t(15;17)
stimulated peripheral blood preparations. Four G-banded metaphases obtained from the bone marrow culture were karyotyped according to the 1971 Paris Conference guidelines [15].
Results Cytogenetic studies of the patient's first bone marrow specimen at our institution revealed 25 metaphases with a h y p e r d i p l o i d karyotype caused by the presence of an extra chromosome #8. Five of these metaphases also exhibited a reciprocal translocation between the long arm of chromosome #15 and the long arm of chromosome #17 (Fig. 2). The patient's karyotype was designated: 80% 47,XY, + 8 and 20% 47,XY, + 8,t(15;17)(q22;q21). As far as we could determine, the breakpoints in this patient were indistinguishable from those seen in t(15;17) in FAB-M3. The metaphases recovered from the unstimulated peripheral blood cultures were also h y p e r d i p l o i d with 47 chromosomes, whereas, the metaphases recovered from the PHA-stimulated peripheral blood cultures were diploid (46,XY). DISCUSSION The presence of t(15;17/ as an acquired abnormality in bone marrow has been associated uniformly with FAB-M3. Even in cases in which t(15;17) occurred during clonal evolution in other types of leukemias, cells with M3 morphology have been apparent [8, 9, 11]. Our patient, thus, was unique in that he had a translocation indistinguishable from the t(15;17) found in FAB-M3 but had a slowly progressive m y e l o d y s p l a s t i c syndrome, CMMoL, clearly distinct from FAB-M3. The precise breakpoints characteristic of t(15;17) m FAB-M3 have been difficult to define [7]. At the Second International Workshop on Chromosomes in Leukemia, the translocation was designated t(15;17)(q25 or 26;q227) [6], but at the Fourth International Workshop t(15;17)(q22;q12 or q21) were considered to be the more
Figure 2
II 1
Giemsa-banded karotype showing 47,XY, + 8, t(15:17)(q22;q21 ).
2
ot 3
4
5
lo
11
12
|tl 16
17
18
l 8
6
13
14
19
20
9
em 15 21
22
XY
292
w.T.
Dalton, Jr., et al.
likely p o s s i b i l i t i e s [7]. E v a l u a t i o n of t h e exact b r e a k p o i n t s in i n d i v i d u a l cases of t(15;17) is f r e q u e n t l y difficult, a n d t h e f i n d i n g s in o u r p a t i e n t m u s t b e c o n s i d e r e d w i t h t h i s i n h e r e n t difficulty in m i n d . In a r e l a t e d s i t u a t i o n , l.,e B e a u et al. u s e d in situ DNA h y b r i d i z a t i o n t e c h n i q u e s to s h o w t h a t a p a t i e n t w i t h a c o n s t i t u t i o n a l t(15;17), p r e v i o u s l y b e l i e v e d to be i d e n t i c a l to t h e t r a n s l o c a t i o n f o u n d in F A B - M 3 [161, a c t u a l l y h a d a c h r o m o s o m e # 1 7 b r e a k p o i n t [17q11) p r o x i m a l to t h a t f o u n d in F A B - M 3 117]. It is p o s s i b l e t h a t s u c h m o l e c u l a r g e n e t i c s t u d i e s , or e v e n p r o p h a s e b a n d i n g t e c h n i q u e s , w o u l d h a v e s h o w n t h a t o u r p a t i e n t ' s b r e a k p o i n t s d i f f e r e d from t h e u s u a l t(15;17) f o u n d in F A B - M 3 . It is still of i n t e r e s t , h o w e v e r , t h a t o u r p a t i e n t h a d t(15;17)(q22;q21) in s o m e of t h i s b o n e m a r r o w m e t a p h a s e s , yet failed to s h o w a n y m o r p h o l o g i c e v i d e n c e of FAB-M3.
REFERENCES 1. Bennett ]M, Catovsky D. Daniel M-T, Flandrm (;, Galton DAG, Gralnick IIR, Suhan C (1976): Proposals for the classification of the acute leukaemias. Br ] Haemat :3:3:451 -458. 2. Testa JR, Golmnb HM, Rowlc;y JD. Vardiman ]W, Sweet DL (1978): HypergranuLar promyeIocytic: leukemia (APL]: Cytogenetic ancl ultrastructural specificity. Blood 52:272-280. :3. Bennett JM, Cat()vsky D, Daniel M-T. Flandrin (;, Galton DAG, Gralnick HR, Sultan C I1980): A variant form of hypergranular promyelocytic leukaemia (M3) Br I Itaemat 44:169-170. 4. (;olomb HM, Rowley JI), Vardiman JW, Testa JR, Butler A (1980): "Microgranular" acute promyelm:ytic: leukemia: A distinct clinical, ultrastructural, and cytogenetic: entity. Blond 55:253-259. 5. l,arson RA, Kondo K, Vardiman ]W, Butler AE. Golomb HM, Rowley JD (1984): Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am ] Med 76:827-841. 6. Seconct International Workshop on Chromosolnes in Leukemia. 1979 (1980): Chromosomes in acute promyelocytic leukemia. Cancer (;enet Cytogenet 2:103-107. 7. l,'ourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Chromosomes in acute prmnyeloc:ytic: leukemia. Cancer (;enet Cytogenet 11:288. 293. 8. Berger R, Bernheim A, Daniel MT. Flandrin G (1983): t(15;17] in a promyelocytic form of chronic myeloi(l leukemia blastic crisis. Cancer G~met Cytogenet 8:149-152. 9. ltogge DE, Misawa S, Schiffer CA, Testa ]R (1984): Promyelocytic hlast crisis in chronic granulocytic leukemia with 15;17 translocation, l,euk Res 8:1019-1023. 10. Bennett ]M. (]atnvsky D, 1)aniel NIT, Flandrin G, Galton DAG. Gralnick, HR, Sultan C (19851: Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103:626-629. 11. Moir D], Pearson ]. Buckle VJ (19841: Acute promyelocytic transformation in a case of a(:ute myelomonocylic leukemia. Cancer Genet Cytogenet 12:359-364. 12. Second International Workshop on Chromosomes in l,eukemia, 1979 (19801: Chromosomes in preleukemia. Cancer Genet Cytogenet 2:108--113. 13. Knapp RH. Dewald GW, Pierre RV (1985): Cytogenetic studies in 174 consecutive patients with preleuke, mi(: or myelndysplastic syndromes. Mayo Clin Pro(: 60:507...516. 14. Bennett JM. Catovsky D, Daniel MT, Handrin G, Gallon DA(;, Gralnick IfR, Sultan (2 (1982): Proposals for the classification of the myelodysplastic syndromes. Br J ttaemat 51:189- 199. 15. Paris Conference (1971): Standarclization in Ituman Cytogenetics. Birth Defects: Original Article Series, VII|:7, 1972. The National Foundatiml, NY. 16. Ferro M'[', San Ronl;.ln C (19811: Constitutional t(15;17). Cant:er Genet (;ytogenet 4:89 91. 17. l,e Beau MM. Rowley ]D, Ferm MT. San Roman C (1{186]: Constitutional t(15;17): clarification of the chr¢)mosomal breakpoints. Cancer Genet Cytogenet 20:175-177.
ABSTRACT: We describe o patient with chronic myclomonocytic h;ukemia who showed trisomy 8 in 100% of his bone marrow metaphases. Of interest was the finding that 20% of the Giemsabanded metaphases also showed t(15;17)(q22;q21), with breukpoints indistinguishable from those seen in cases of acute progranulocytic leukemia (APL). The patient showed no morpholagic or clinical evidence of APL, and he died after 6 months, with no evidence that the disease had progressed to acute leukemia. Although cytogeneticully the breakpoints appeared to he the same as those in APt,, we suspect that this patient's translncation may have differed at the molecular level from the t(15;17) commonly seen in API..
INTRODUCTION
There is a very strong association between t(15;17)(q22;q21) and acute progranulocytic leukemia (APL) (FAB classification M3 [1]) in both its hypergranular [2] and its variant, or microgranular form [3, 4]. Most patients with API,-M3 can be shown to have t(15;17) in their bone marrow metaphases. I,arson et al. [5] have demonstrated this translocation in all of their M3 patients, although other investigators find t(15;17) infrequently [6, 7]. This variability is the result, at least in part, of differences in the way the individual laboratories process bone marrow samples, with longer periods of culture favoring the recovery of metaphases with t(15;17) [7]. The experience with regard to the converse relationship, in contrast, is quite uniform: when t(15;17) is found as an acquired abnormality in hematologic malignancies, the bone marrow predictably shows abnormal progranulocytes with M3 morphology. This has held true even in u n u s u a l circumstances. Two patients with Phpositive chronic: granulocytic leukemia developed blast crisis, at which time they showed t(15;17) in more than half of their Ph-positive metaphases, and sllowed M3 morphology in their bone marrows [8, 9]. In another instance, a patient with acute myelomonocytic leukemia with abnormal eosinopbils (t"AB M4Eo [10]) and inv(16}(p13q22) had a minor related clone with both inv(16}(p13q22) and t(15;17)
From the Division of Laboratory Medicine, The Universityof Texas. M. D. Anderson llospital and Tumor Institute.ftouston, TX Address requests for reprints to Dr. Willard T. Dalton, Jr. Division of l.obaratory Medicine, Box 73, M. D. Anderson Hospital and Tumor Institute, 1515 Holcombe Blvd., Houston, TX 77030. Received March 16, 1987; accepted December 14. 1987.
287 'V)1988 W. T. Dalton.Jr.
Cancer (.;enet Cytogenet32:287-292 [1.q881
288
W . T . Dalton, Jr., et al. and a corresponding minor population of abnormal progranulocytes with M3 morphology in his bone marrow [11[. In large series reporting the cytogenetics of patients with preleukemic or m y e l o d y s p l a s t i c syndromes (MDS), one notable feature is the consistent failure to find t(15;17) [12, 13J. We now report a patient with trisomy 8 and a related clone with trisomy 8 and t(15;17) who had a slowly progressing MDS for more than 6 months, and who died without apparent transformation to acute leukemia.
CASE REPORT The patient was a 67-year-old man who was referred to M. D. Anderson Hospital in December 1977 with a diagnosis of preleukemia. During the previous summer he had noticed ecchymoses on his skin, and they had been increasing in number. He had diabetes mellitus, mild emphysema, and severe food and drug allergies. Physical examination failed to reveal l y m p h a d e n o p a t h y or hepatosplenomegaly. Initial peripheral blood counts showed a hemoglobin count of 11.8 g/dl, mean corpuscular volume 109 fl, platelet count 56 × 10*~/l,, and a leukocyte count of 8.1 × 10~J/L, with 25% mature neutrophils, 36% lymphocytes, 26% monocytes, 6% eosinophils, 1% basophils, 5% metamyelocytes, and 1% myelocytes. Prothrombin time, partial thromboplastin time, and levels of fibrinogen and fibrin degradation products were within normal limits. His leukocyte alkaline phosphatase (LAP) score was low at 1. His vitamin B,2 level was 888 pg/ml (n = 250 to 1000) and folate level 25.7 ng/ml (n = 4 to 16) (both done at the referring institution). Total serum protein was 7.8 g/dl, and albumin 4.5 g/dl. Serum i m m u n o g l o b u l i n assays showed: IgG 1669 mg/dl (n = 650 to 1750), IgA 285 mg/dl (n - 75 to 330), and lgM 43 mg/dl (n = 30 to 225). Thus, he had a borderline high IgG; a serum protein electrophoresis indicated polyclonal gamma globulins. A bone marrow aspirate showed a 70% cellularity with 6% blasts, 4% monocytes, and dysplasias of all three cell lines, consistent with a m y e l o d y s p l a s t i c process (Fig. 1). No Auer rods or abnormal progranulocytes of the type seen in FAB-M3 were identified. Based on the peripheral blood and bone marrow findings, this process was classified as chronic myelomonocytic leukemia (CMMoL) in accordance with FAB criteria [14]. Four additional bone marrow aspirates obtained during the next 6 months showed an increasing percentage of monocytes, but no other substantial changes (Table 1). The peripheral blood leukocyte counts rose steadily during this time, with an increasing absolute monocytosis. The patient died in July 1978 without clinical evidence of transformation to acute leukemia, although no bone marrow aspirates were obtained during the final 2 months of his life. CYTOGENETIC STUDIES Methods Chromosome studies were performed on the initial bone marrow aspirate and peripheral blood sample obtained in December 1977. Briefly, these studies included culturing the bone marrow cells overnight at 37°C and culturing the peripheral blood cells for 24 and 48 hours without stimulation and for 72 hours with phytohemagglutinin (PHA) stimulation. G-banded chromosomes were obtained by exposing the air-dried preparations made from the bone marrow culture to a 1.5 minute trypsin pretreatment followed by 1.5 minute Giemsa staining at pH 6.8. Twentyfive well-spread metaphases from the bone marrow preparations were analyzed, seven from the unstimulated peripheral blood preparations and 16 from the PHA-
C M M o L w i t h T r i s o m y 8 a n d t(15;17)
289
,/
t,
F i g u r e 1 Bone marrow smear. (A) Granulopoiesis is shifted to the le.ft and some hyposegmented neutrophils are present (arrows). Blasts are slightly i,lcreased (arrowhead). (B] Megakaryocytes tend to be small and hyposegmented. No cells resembling lhe abnormal progranulocytes ~f FAB-M3 are present. (Wright-(;iemsa stain)
0 0 -
35 40 -
59 57 110
35.5 42.3 50.0
4178 5176 6178
"Cellularity was visually estimated from histologic sections of aspirated bone marrow particles,
0 -
Blasts (%)
26 -
(%)
56 -
Monocytes
8.1 -
(X lOgiL)
12177 l/78
Platelets
blood
over time
Peripheral
data on CMMoL patient
WBC (x10%)
Hematologic
Date (mo/yr)
Table 1
70 80 75 70 -
Cellularity
(%)’
6 12 10 7 -
Blasts (%)
Bone marrow
4 4 11 13 -
Monocytes
(%)
0
s:
291
CMMoL with Trisomy 8 and t(15;17)
stimulated peripheral blood preparations. Four G-banded metaphases obtained from the bone marrow culture were karyotyped according to the 1971 Paris Conference guidelines [15].
Results Cytogenetic studies of the patient's first bone marrow specimen at our institution revealed 25 metaphases with a h y p e r d i p l o i d karyotype caused by the presence of an extra chromosome #8. Five of these metaphases also exhibited a reciprocal translocation between the long arm of chromosome #15 and the long arm of chromosome #17 (Fig. 2). The patient's karyotype was designated: 80% 47,XY, + 8 and 20% 47,XY, + 8,t(15;17)(q22;q21). As far as we could determine, the breakpoints in this patient were indistinguishable from those seen in t(15;17) in FAB-M3. The metaphases recovered from the unstimulated peripheral blood cultures were also h y p e r d i p l o i d with 47 chromosomes, whereas, the metaphases recovered from the PHA-stimulated peripheral blood cultures were diploid (46,XY). DISCUSSION The presence of t(15;17/ as an acquired abnormality in bone marrow has been associated uniformly with FAB-M3. Even in cases in which t(15;17) occurred during clonal evolution in other types of leukemias, cells with M3 morphology have been apparent [8, 9, 11]. Our patient, thus, was unique in that he had a translocation indistinguishable from the t(15;17) found in FAB-M3 but had a slowly progressive m y e l o d y s p l a s t i c syndrome, CMMoL, clearly distinct from FAB-M3. The precise breakpoints characteristic of t(15;17) m FAB-M3 have been difficult to define [7]. At the Second International Workshop on Chromosomes in Leukemia, the translocation was designated t(15;17)(q25 or 26;q227) [6], but at the Fourth International Workshop t(15;17)(q22;q12 or q21) were considered to be the more
Figure 2
II 1
Giemsa-banded karotype showing 47,XY, + 8, t(15:17)(q22;q21 ).
2
ot 3
4
5
lo
11
12
|tl 16
17
18
l 8
6
13
14
19
20
9
em 15 21
22
XY
292
w.T.
Dalton, Jr., et al.
likely p o s s i b i l i t i e s [7]. E v a l u a t i o n of t h e exact b r e a k p o i n t s in i n d i v i d u a l cases of t(15;17) is f r e q u e n t l y difficult, a n d t h e f i n d i n g s in o u r p a t i e n t m u s t b e c o n s i d e r e d w i t h t h i s i n h e r e n t difficulty in m i n d . In a r e l a t e d s i t u a t i o n , l.,e B e a u et al. u s e d in situ DNA h y b r i d i z a t i o n t e c h n i q u e s to s h o w t h a t a p a t i e n t w i t h a c o n s t i t u t i o n a l t(15;17), p r e v i o u s l y b e l i e v e d to be i d e n t i c a l to t h e t r a n s l o c a t i o n f o u n d in F A B - M 3 [161, a c t u a l l y h a d a c h r o m o s o m e # 1 7 b r e a k p o i n t [17q11) p r o x i m a l to t h a t f o u n d in F A B - M 3 117]. It is p o s s i b l e t h a t s u c h m o l e c u l a r g e n e t i c s t u d i e s , or e v e n p r o p h a s e b a n d i n g t e c h n i q u e s , w o u l d h a v e s h o w n t h a t o u r p a t i e n t ' s b r e a k p o i n t s d i f f e r e d from t h e u s u a l t(15;17) f o u n d in F A B - M 3 . It is still of i n t e r e s t , h o w e v e r , t h a t o u r p a t i e n t h a d t(15;17)(q22;q21) in s o m e of t h i s b o n e m a r r o w m e t a p h a s e s , yet failed to s h o w a n y m o r p h o l o g i c e v i d e n c e of FAB-M3.
REFERENCES 1. Bennett ]M, Catovsky D. Daniel M-T, Flandrm (;, Galton DAG, Gralnick IIR, Suhan C (1976): Proposals for the classification of the acute leukaemias. Br ] Haemat :3:3:451 -458. 2. Testa JR, Golmnb HM, Rowlc;y JD. Vardiman ]W, Sweet DL (1978): HypergranuLar promyeIocytic: leukemia (APL]: Cytogenetic ancl ultrastructural specificity. Blood 52:272-280. :3. Bennett JM, Cat()vsky D, Daniel M-T. Flandrin (;, Galton DAG, Gralnick HR, Sultan C I1980): A variant form of hypergranular promyelocytic leukaemia (M3) Br I Itaemat 44:169-170. 4. (;olomb HM, Rowley JI), Vardiman JW, Testa JR, Butler A (1980): "Microgranular" acute promyelm:ytic: leukemia: A distinct clinical, ultrastructural, and cytogenetic: entity. Blond 55:253-259. 5. l,arson RA, Kondo K, Vardiman ]W, Butler AE. Golomb HM, Rowley JD (1984): Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am ] Med 76:827-841. 6. Seconct International Workshop on Chromosolnes in Leukemia. 1979 (1980): Chromosomes in acute promyelocytic leukemia. Cancer (;enet Cytogenet 2:103-107. 7. l,'ourth International Workshop on Chromosomes in Leukemia, 1982 (1984): Chromosomes in acute prmnyeloc:ytic: leukemia. Cancer (;enet Cytogenet 11:288. 293. 8. Berger R, Bernheim A, Daniel MT. Flandrin G (1983): t(15;17] in a promyelocytic form of chronic myeloi(l leukemia blastic crisis. Cancer G~met Cytogenet 8:149-152. 9. ltogge DE, Misawa S, Schiffer CA, Testa ]R (1984): Promyelocytic hlast crisis in chronic granulocytic leukemia with 15;17 translocation, l,euk Res 8:1019-1023. 10. Bennett ]M. (]atnvsky D, 1)aniel NIT, Flandrin G, Galton DAG. Gralnick, HR, Sultan C (19851: Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103:626-629. 11. Moir D], Pearson ]. Buckle VJ (19841: Acute promyelocytic transformation in a case of a(:ute myelomonocylic leukemia. Cancer Genet Cytogenet 12:359-364. 12. Second International Workshop on Chromosomes in l,eukemia, 1979 (19801: Chromosomes in preleukemia. Cancer Genet Cytogenet 2:108--113. 13. Knapp RH. Dewald GW, Pierre RV (1985): Cytogenetic studies in 174 consecutive patients with preleuke, mi(: or myelndysplastic syndromes. Mayo Clin Pro(: 60:507...516. 14. Bennett JM. Catovsky D, Daniel MT, Handrin G, Gallon DA(;, Gralnick IfR, Sultan (2 (1982): Proposals for the classification of the myelodysplastic syndromes. Br J ttaemat 51:189- 199. 15. Paris Conference (1971): Standarclization in Ituman Cytogenetics. Birth Defects: Original Article Series, VII|:7, 1972. The National Foundatiml, NY. 16. Ferro M'[', San Ronl;.ln C (19811: Constitutional t(15;17). Cant:er Genet (;ytogenet 4:89 91. 17. l,e Beau MM. Rowley ]D, Ferm MT. San Roman C (1{186]: Constitutional t(15;17): clarification of the chr¢)mosomal breakpoints. Cancer Genet Cytogenet 20:175-177.